N-(2-arylethyl)benzylamines as antagonists of the 5-ht6 receptor

ABSTRACT

The present invention provides compounds of formula (I), which are antagonists of the 5-HT 6  receptor.

The present invention relates to the field of pharmaceutical and organicchemistry and is concerned with compounds which are antagonists of the5-HT₆ receptor.

The 5-HT₆ receptor is a member of the G-protein coupled receptorsuperfamily of serotonin receptors, and, like the 5-HT₄ and 5-HT₇receptors, it is positively coupled to adenylate cyclase.¹ The rat 5-HT₆receptor was first cloned in 1993^(2,3) and the cloning of the humanhomologue, to which it shares a 89% sequence identity, was reported in1996.⁴ The localization of 5-HT₆ receptors in rat brain has been studiedusing mRNA quantification by Northern analysis and RT-PCR,immunohistochemistry, and autoradiography.^(2,3,5,6,7,8) These methodshave consistently found high levels of the receptor in olfactorytubercle, hippocampus, striatum, nucleus accumbens, and corticalregions. 5-HT₆ receptors are either absent or present in very low levelsin peripheral tissues.^(2,3)

To date, there are no known high affinity, selective agonists at the5-HT₆ receptor. Serotonin itself has only moderate affinity for the5-HT₆ receptor (Ki=65 nM) and the most selective agonist reported todate, N,N-dimethyl-2-ethyl-5-methoxytryptamine, has Ki=81 nM and only3.5-fold selectivity versus the 5-HT_(2A) receptor.⁹

Much of the recent interest in the 5-HT₆ receptor is due to theobservation that several psychotropic agents are high affinityantagonists at the human 5-HT₆ receptor.^(4,10) These compounds includeamitriptyline (Ki=65 nM) and the atypical antipsychotics clozapine(Ki=9.5 nM), olanzapine (Ki=10 nM), and quetiapine (33 nM). None ofthese compounds, however, are selective. The first selective 5-HT₆receptor antagonists reported are Ro 04-6790 and Ro 63-0563. Theirusefulness is limited by their moderate affinity (Ki=50 nM and 12 nM,respectively) and poor pharmacokinetics.¹¹ A series of 5-HT₆ receptorantagonists, culminating in SB-271,046, has been reported.¹² Thiscompound has high affinity (Ki=1.2 nM) and selectivity (>200-foldversus >55 receptors, enzymes and ion channels) and is 80% bioavailable.A selective radioligand [¹²⁵I]-SB-258,585 has been used for radioligandbinding and autoradiographic studies.^(13,14) These compounds are usefultools for preclinical studies on the 5-HT₆ receptor.

The rationale for the use of selective 5-HT₆ receptor antagonists totreat cognitive dysfunction is based on three lines of reasoning: theability of selective 5-HT₆ receptor antagonists to modulate cholinergicand glutamatergic neuronal function, clinical studies of the atypicalantipsychotics clozapine and olanzapine on cognitive function, theactivity of selective 5-HT₆ receptor antagonists in animal models ofcognitive function.

Selective 5-HT₆ receptor antagonists modulate cholinergic andglutamatergic neuronal function. Cholinergic and glutamatergic neuronalsystems play important roles in cognitive function. Cholinergic neuronalpathways are known to be important to memory formation andconsolidation. Centrally acting anticholinergic agents impair cognitivefunction in animal and clinical studies and loss of cholinergic neuronsis one of the hallmarks of Alzheimer's disease. Conversely, stimulationof cholinergic function has been known to improve cognitive performanceand the only two agents currently approved for the treatment ofcognitive deficit in Alzheimer's disease, tacrine and donepezil, areboth acetylcholinesterase inhibitors. The glutamatergic system in theprefrontal cortex is also known to be involved in cognitivefunction.^(26,27)

Blocking 5-HT₆ receptor function has been shown to elicit procholinergiceffects in vivo. Administration (icv) to rats of antisenseoligonucleotides targeting the 5-HT₆ receptor sequence induced yawningand stretching behavior that was blocked by the cholinergic antagonistatropine.¹⁵ The selective 5-HT₆ receptor antagonist Ro 046790 inducedstretching behavior in a dose-dependent manner. This behavior wasblocked by the centrally acting anticholinergic agents scopolamine andatropine but not by methyl-scopolamine at doses known to be peripherallyselective.¹⁶ Ro 04-6790 was also shown to block the rotational behaviorinduced by scopolamine administration to rats with unilateralnigrostriatal 6-OH-DA lesions. It did not block rotational behaviorinduced by L-DOPA or amphetamine.¹⁷ Ro 04-6790 reversed scopolamineinduced performance deficits in the object recognition test, a model ofcognitive function. Another selective 5-HT₆ receptor antagonist,SB-271046, potentiated the yawning behavior induced by thecholinesterase inhibitor physostigmine.¹⁸ These studies suggest that5-HT₆ receptor blockade facilitates cholinergic transmission. In in vivomicrodialysis studies, SB-271,046 (10 mg/kg, sc) increases glutamaterelease in the prefrontal cortex through a neuronal mechanism.²⁵

Clinical studies of the atypical antipsychotics clozapine and olanzapineon cognitive function. The atypical antipsychotics clozapine andolanzapine are both high affinity, albeit nonselective, 5-HT₆ receptorantagonists.⁴ On the other hand, risperidone and the typicalantipsychotic haloperidol do not have significant affinity for the 5-HT₆receptor. Clinical differences seen with these sets of drugs may beattributable to 5-HT₆ receptor blockade. Goldberg et al. reported nobeneficial cognitive effect of clozapine treatment in a small (N=15)trial in treatment resistant schizophrenics.¹⁹ In contrast, Meltzer etal. in a larger study of treatment-resistant schizophrenics (N=36),observed improvements in several domains of neuropsychological functionat six weeks and six months following initiation of clozapine treatment.In non-treatment resistant schizophrenics, clozapine was more effectivethan placebo in improving cognitive function by several measures.²¹ Thiseffect was seen at six months and persisted throughout the 12 monthstudy. The effect of olanzapine, risperidone, and haloperidol oncognitive function has been compared in a multicenter, double blindstudy in schizophrenics.²² The olanzapine group showed a statisticallysignificant improvement in cognitive function over either haloperidol orrisperidone treatment. This effect was apparent after 6 weeks treatmentand continued throughout the 54 weeks of the study. Animal studiessuggest that these effects could be mediated through the release ofacetylcholine in the prefrontal cortex.²³

Activity of selective 5-HT₆ receptor antagonists in animal models ofcognitive function. With the recent development of the selective 5-HT₆receptor antagonists Ro-04,6790 and SB-271,046, there have been severalreports on the activity of these compounds in models of cognitivefunction. The selective 5-HT₆ receptor antagonist SB-271,046 improvedperformance in the Morris water maze.²⁴ These results are consistentwith the finding that chronic icv administration of antisenseoligonucleotides directed toward the 5-HT₆ receptor sequence led toimprovements in some measures of performance in the Morris water maze.¹⁶SB-271,046 treatment also led to improvements in the spatial alternationoperant behavior test in aged rats.²⁴

The compounds of the present invention are selective, high affinityantagonists of 5-HT₆, and thus, provide a valuable treatment for 5-HT₆receptor mediated disorders.

Background References

-   1. Branchek, T. A., et al. (2000). Annu Rev Pharmacol Toxicol 40:    319-34.-   2. Monsma, F. J., Jr., et al. (1993). Mol Pharmacol 43(3): 320-7.-   3. Ruat, M., et al. (1993). Biochem Biophys Res Commun 193(1):    268-76.-   4. Kohen, R., et al. (1996). J Neurochem 66(1): 47-56.-   5. Ward, R. P., et al. (1996). J Comp Neurol 370(3): 405-14.-   6. Ward, R. P., et al. (1995). Neuroscience 64(4): 1105-11.-   7. Gerard, C., et al. (1997). Brain Res 746(1-2): 207-19.-   8. Gerard, C., et al. (1996). Synapse 23(3): 164-73.-   9. Glennon, R. A., et al. (2000). J Med Chem 43(5): 1011-8.-   10. Roth, B. L., et al. (1994). J Pharmacol Exp Ther 268(3):    1403-10.-   11. Sleight, A. J., et al. (1998). Br J Pharmacol 124(3): 556-62.-   12. Routledge, C., et al. (2000). Br. J. Pharmacol. 130(7): 1606.-   13. Hirst, W. D., et al. (1999). Br. J. Pharmacol. Suppl. ((in    press)).-   14. Hirst, W. D., et al. (2000). Br. J. Pharmacol. 130: 1597.-   15. Bourson, A., et al. (1995). J Pharmacol Exp Ther 274(1): 173-80.-   16. Bentley, J. C., et al. (1999). Br J Pharmacol 126(7): 1537-42.-   17. Bourson, A., et al. (1998). Br J Pharmacol 125(7): 1562-6.-   18. Routledge, C., et al. (1999). Br. J. Pharmacol. 127(Suppl.):    21P.-   19. Goldberg, T. E., et al. (1993). Br J Psychiatry 162: 43-8.-   20. Hagger, C., et al. (1993). Biol Psychiatry 34(10): 702-12.-   21. Lee, M. A., et al. (1994). J Clin Psychiatry 55 Suppl B: 82-7.-   22. Purdon, S. E., et al. (2000). Arch Gen Psychiatry 57(3): 249-58.-   23. Parada, M. A., et al. (1997). J Pharmacol Exp Ther 281(1):    582-8.-   24. Rogers, D. C., et al. (1999). Br J Pharmcol 127(suppl.): 22P.-   25. Dawson, L. A., et al. (2000). Br J Pharmacol 130(1): 23-6.-   26. Dudkin, K. N., et al. (1996). Neurosci Behav Physiol 26(6):    545-51.-   27. Koechlin, E., et al. (1999). Nature 399(6732): 148-51.

The present invention provides compounds of formula I:

wherein

-   X is selected from the group consisting of —O—, —NH—, —S—, —SO₂—,    —CH₂—, —CH(F)—, —CH(OH)—, and —C(O)—;-   R₁ is selected from the group consisting of optionally substituted    phenyl, optionally substituted naphthyl, optionally substituted 5 to    6 membered monocyclic aromatic heterocycle having one heteroatom    selected from the group consisting of nitrogen, oxygen, and sulfur    and which 5 to 6 membered monocyclic aromatic heterocycle is    optionally benzofused;-   R₂ is selected from the group consisting of hydrogen and C₁-C₃    alkyl;-   R₃ is selected from the group consisting of hydrogen, fluoro, and    methyl;-   R₄ is selected from the group consisting of hydrogen, allyl, C₂-C₄    alkyl, fluorinated C₂-C₄ alkyl, optionally substituted phenyl,    optionally substituted phenylsulfonyl, optionally substituted    benzyl, and optionally substituted 5 to 6 membered monocyclic    aromatic heterocycle having one or two heteroatoms selected from the    group consisting of nitrogen, oxygen, and sulfur, provided that R₄    is not optionally substituted phenylsulfonyl when X is —SO₂—, —CH₂—,    —CH(F)—, —CH(OH)—, or —C(O)—; and    pharmaceutically acceptable salts thereof.

The present invention also provides compounds of formula II:

wherein

-   Y is selected from the group consisting of O, NH, and NR₉, wherein    R₉ is selected from the group consisting of C₁-C₄ alkyl, and    optionally substituted phenyl;-   R₅ and R₆ are hydrogen or taken together with the atoms to which    they are attached form a benzo ring, provided that R₅ and R₆ are    hydrogen when Y is NR₉;-   R₇ is selected from the group consisting of optionally substituted    phenyl, optionally substituted naphthyl, optionally substituted 5 to    6 membered monocyclic aromatic heterocycle having one heteroatom    selected from the group consisting of nitrogen, oxygen, and sulfur    and which 5 to 6 membered monocyclic aromatic heterocycle is    optionally benzofused;-   R₈ is selected from the group consisting of hydrogen and C₁-C₃    alkyl; and pharmaceutically acceptable salts thereof.

The present invention also provides for novel pharmaceuticalcompositions, comprising: a compound of the formula I or II and apharmaceutically acceptable diluent.

Because the compounds of formula I and II are antagonists of 5-HT₆receptor, the compounds of formula I and B are useful for the treatmentof a variety of disorders. Thus, in another embodiment the presentinvention provides methods of treating disorders associated with 5-HT₆,comprising: administering to a patient in need thereof an effectiveamount of a compound of formula I or II. That is, the present inventionprovides for the use of a compound of formula I or II and pharmaceuticalcompositions thereof for the treatment disorders associated with 5-HT₆.More specifically, the present invention provides a method of treatingdisorders selected from the group consisting of cognitive disorders,age-related cognitive disorder, mild cognitive impairment, mooddisorders (including depression, mania, bipolar disorders), psychosis(in particular schizophrenia), anxiety (particularly includinggeneralized anxiety disorder, panic disorder, and obsessive compulsivedisorder), idiopathic and drug-induced Parkinson's disease, epilepsy,convulsions, migraine (including migraine headache), substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.), sleep disorders (including narcolepsy), attentiondeficit/hyperactivity disorder, conduct disorder, learning disorders,dementia (including Alzheimer's disease and AIDS-induced dementia),Huntington's Chorea, cognitive deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemicneuronal damage, vascular dementia, multi-infarct dementia, amylotrophiclateral sclerosis, and multiple sclerosis, comprising: administering toa patient in need thereof an effective amount of a compound of formula Ior an effective amount of a compound of formula II.

In addition, the present invention also provides processes for preparingthe compounds of formula I and II and intermediate thereof.

As used herein, the following terms have the meanings indicated:

The term “C₁-C₃ alkyl” refers to a straight or branched alkyl chainhaving from one to three carbon atoms, and includes methyl, ethyl,propyl, and iso-propyl.

The term “optionally substituted phenyl” refers to a radical of theformula

wherein R_(a) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy,halogen, benzyloxy, carboxy, C₁-C₄ alkoxycarbonyl, amido, N—(C₁-C₄alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy,nitro, and phenyl optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy,halogen, cyano, and trifluoromethyl.

The term “optionally substituted naphthyl” refers to a radical of theformula

wherein R_(c) is from 1 to 2 groups independently selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano,trifluoromethyl, and nitro.

The term “optionally substituted 5 to 6 membered monocyclic aromaticheterocycle having one heteroatom selected from the group consisting ofnitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclicaromatic heterocycle is optionally benzofused” refers to radicals of theformula

wherein Q₁ is selected from the group consisting of —O—, —S—, and—NR_(g)— wherein R_(g) is selected from the group consisting of hydrogenand C₁-C₄ alkyl; and Q₂ is —N═, R_(d), each R_(e), and R_(f) are eachindependently selected from the group consisting of hydrogen, C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, cyano, and trifluoromethyl, or R_(d) andR_(e) (or one of R_(e)) are taken together with the atoms to which theyare attached to form an benzo ring which benzo ring is optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of hydrogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen,carboxy, C₁-C₄ alkoxycarbonyl, amido, N—(C₁-C₄ alkyl)amido, amino,(C₁-C₄ alkyl)amino, acylamino wherein the acyl group is selected fromthe group consisting of C₁-C₄ alkyl and phenyl; cyano, nitro,sulfonylamido, phenyl optionally substituted with C₁-C₄ alkyl, C₁-C₄alkoxy, halogen, cyano, and trifluoromethyl; phenoxy, benzyloxy,—NHS(O)₂R_(h), wherein R_(h) is selected from the group consisting ofC₁-C₄ alkyl and phenyl; and —S(O)_(p)R_(i), wherein p is 0, 1, or 2 andR_(i) is selected from the group consisting of C₁-C₄ alkyl and phenyloptionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano,and trifluoromethyl; and R_(f) is selected from the group consisting ofhydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, and halogen. Theterm specifically includes furyl, thienyl, pyrrolyl, pyridyl,benzofuryl, benzothienyl, indolyl and quinolinyl; each optionallysubstituted as described above.

The term “fluorinated C₂-C₄ alkyl” refers to a straight or branchedalkyl chain having from two to four carbon atoms substituted with one ormore fluorine atoms. The term includes 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl,3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,2,2,3,3-tetrafluoropropyl, 4,4,4-trifluorobutyl,3,3,4,4,4-pentafluorobutyl, and the like.

The term “optionally substituted phenylsulfonyl” refers to a radical ofthe formula

wherein R_(j) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano,trifluoromethyl, nitro, and phenyl.

The term “optionally substituted benzyl” refers to a radical of theformula

wherein R_(k) is from 1 to 3 groups independently selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, nitro,trifluoromethyl, and halogen.

The term “optionally substituted 5 to 6 membered monocyclic aromaticheterocycle having one or two heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur” refers to radicals of theformula

wherein Q₃ is selected from the group consisting of —O—, —S—, and—NR_(g′)— wherein R_(g′) is selected from the group consisting ofhydrogen and C₁-C₄ alkyl; and Q₄ and Q₅ are —CR_(m), wherein each R_(m)is independently selected from the group consisting of hydrogen, C₁-C₄allyl, halogen, and trifluoromethyl or one or both of Q₄ and Q₅ is —N═;and wherein one or two of Q₆ are —N═, while the others are —CR_(n);wherein each R_(n) is independently selected from the group consistingof hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano, nitro, andtrifluoromethyl. The term specifically includes furyl, thienyl,thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,isoxazolyl, thioisoxazolyl, pyridyl, pyrimidyl, pyridazinyl, andpyrazidinyl; each optionally substituted as described above.

The term “C₁-C₄ alkyl” refers to a straight or branched alkyl chainhaving from one to four carbon atoms, and includes methyl, ethyl,propyl, iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.

The term “C₂-C₄ alkyl” refers to a straight or branched alkyl chainhaving from two to four carbon atoms, and includes ethyl, propyl,iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.

The term “C₁-C₄ alkoxy” refers to a straight or branched alkyl chainhaving from one to four carbon atoms attached to an oxygen atom, andincludes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy,sec-butoxy, and t-butoxy.

The term “halogen” refers to a chloro, fluoro, bromo or iodo atom.

The term “pharmaceutically-acceptable addition salt” refers to an acidaddition salt.

The compound of formula I or II and the intermediates described hereinform pharmaceutically acceptable acid addition salts with a wide varietyof organic and inorganic acids and include the physiologicallyacceptable salts which are often used in pharmaceutical chemistry. Suchsalts are also part of this invention. A pharmaceutically-acceptableaddition salt is formed from a pharmaceutically-acceptable acid as iswell known in the art. Such salts include the pharmaceuticallyacceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19(1977) which are known to the skilled artisan. Typical inorganic acidsused to form such salts include hydrochloric, hydrobromic, hydriodic,nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric,pyrophosphoric, and the like. Salts derived from organic acids, such asaliphatic mono and dicarboxylic acids, phenyl substituted alkanoicacids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, may also be used. Suchpharmaceutically acceptable salts thus include chloride, bromide,iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate,maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,isonicotinate, oxalate, phthalate, teraphthalate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,tartrate, and the like.

As with any group of pharmaceutically active compounds, some groups arepreferred in their end use application. Preferred embodiments of thepresent invention are given for the compounds of formula I below:

Compounds in which wherein X is selected from the group consisting of—O—, —NH—, and —S— are preferred, with compounds in which X is —O— beingmore preferred.

Compounds in which R₁ is optionally substituted phenyl or optionallysubstituted 5 to 6 membered monocyclic aromatic heterocycle having oneheteroatom selected from the group consisting of nitrogen, oxygen, andsulfur and which 5 to 6 membered monocyclic aromatic heterocycle isoptionally benzofused are preferred.

When R₁ is optionally substituted phenyl preferred substituents are 1 to3 groups independently selected from the group consisting of hydrogen,C₁-C₄ alkyl, halogen, benzyloxy, carboxy, C₁-C₄ alkoxycarbonyl, amido,N—(C₁-C₄ alkyl)amido, sulfonylamido, cyano, trifluoromethyl,trifluoromethoxy, nitro, and phenyl optionally substituted with C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, cyano, and trifluoromethyl.

When R₁ is optionally substituted phenyl more preferred substituents are1 to 3 groups independently selected from the group consisting ofhydrogen, C₁-C₄ alkyl, halogen, cyano, and trifluoromethyl.

Compounds in which R₃ is hydrogen or fluorine are preferred.

Compound in which R₁ is optionally substituted 5 to 6 memberedmonocyclic aromatic heterocycle having one heteroatom selected from thegroup consisting of nitrogen, oxygen, and sulfur and which 5 to 6membered monocyclic aromatic heterocycle is optionally benzofused, thecompounds which are benzo fused are preferred, with indolyl beingpreferred, and indol-3-yl being even more preferred.

When R₁ is indol-3-yl, preferred groups are depicted as the radicalbelow:

a) R_(o) is selected from the group consisting of hydrogen and C₁-C₄alkyl, with hydrogen being more preferred;b) R_(p) is selected from the group consisting of hydrogen and C₁-C₄alkyl, with hydrogen being more preferred;c) R_(q) is selected from the group consisting of hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, and halogen, with hydrogen being more preferred;d) R_(q′) is selected from the group consisting of hydrogen, C₁-C₄alkyl, C₁-C₄ alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,trifluoromethyl halogen, and —S(O)_(p)R_(i) wherein p is 2 and R_(i) isphenyl optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy,trifluoromethyl, with halogen being more preferred;e) R_(q″) is selected from the group consisting of hydrogen, C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, nitro, cyano, trifluoromethyl, and—S(O)_(p)R_(i), wherein p 2 and R_(i) is phenyl optionally substitutedwith C₁-C₄ alkyl, with halogen being more preferred; andf) R_(q′″) is selected from the group consisting of hydrogen, C₁-C₄alkyl, C₁-C₄ alkoxy, halogen, trifluoromethyl, cyano, and nitro, withhydrogen and halogen being preferred.

Compounds in which R₄ is selected from the group consisting of C₂-C₄alkyl, fluorinated C₂-C₄ alkyl and optionally substituted phenyl arepreferred.

When R₄ is C₂-C₄ alkyl, particularly preferred groups include propyl,isopropyl, and butyl.

When R₄ is fluorinated C₂-C₄ alkyl, preferred groups include2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl,3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,and 2,2,3,3-tetrafluoropropyl.

When R₄ is optionally substituted phenyl preferred groups include 1 to 3groups independently selected from the group consisting of hydrogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano, and trifluoromethyl.

Preferred embodiments of the present invention are given for thecompounds of formula II below:

Compounds in which R₇ is optionally substituted phenyl or optionallysubstituted 5 to 6 membered monocyclic aromatic heterocycle having oneheteroatom selected from the group consisting of nitrogen, oxygen, andsulfur and which 5 to 6 membered monocyclic aromatic heterocycle isoptionally benzofused are preferred.

When R₇ is optionally substituted phenyl preferred substituents are 1 to3 groups independently selected from the group consisting of hydrogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, cyano, trifluoromethoxy, andtrifluoromethyl.

Compounds in which R₇ is optionally substituted 5 to 6 memberedmonocyclic aromatic heterocycle having one heteroatom selected from thegroup consisting of nitrogen, oxygen, and sulfur and which 5 to 6membered monocyclic aromatic heterocycle is optionally benzofused, thecompounds which are benzo fused are preferred, with indolyl beingpreferred, and indol-3-yl being even more preferred, with the indol-3-yldepicted above for formula I being more preferred.

Preferred compounds of formula II having the points of attachmentdepicted below:

While only compounds of formula I are depicted, the compounds of formulaI and II are prepared as described in Schemes A and B below. In theSchemes below all substituents, unless otherwise indicated, are aspreviously defined, and all starting materials and reagents are wellknown and appreciated in the art and readily available or prepared bymethods described herein. In the Schemes below, it is understood thatprotecting groups can be used, where appropriate to allow forelaboration of a portion of the compounds of formula I or II. Theselection, use, and removal of suitable protecting groups is well knownand appreciated in the art (Protecting Groups in Organic Synthesis,Theodora Greene (Wiley-Interscience)).

Scheme A depicts alternative methods for the preparation of compounds offormula I by reductive amination.

In one alternative of Scheme A, step a, an appropriate compound offormula (1) is contacted with an appropriate compound of formula (2) ina reductive amination reaction to give a compound of formula I. Anappropriate compound of formula (1) is one in which R₁ and R₂ are asdesired in the final product of formula I or give rise to groups desiredin the final product of formula I. An appropriate compound of formula(2) is one in which X, R₃, and R₄ are as desired in the final product offormula I, or give rise to groups desired in the final product offormula I.

In another alternative of Scheme A, step a, an appropriate compound offormula (3) is contacted with an appropriate compound of formula (4) ina reductive amination reaction to give a compound of formula I. Anappropriate compound of formula (3) is one in which R₁ and R₂ are asdesired in the final product of formula I or give rise to groups desiredin the final product of formula I. An appropriate compound of formula(4) is one in which X, R₃, and R₄ are as desired in the final product offormula I or give rise to groups desired in the final product of formulaI.

The reductive amination depicted in Scheme A, step a, can be carried outunder a variety of conditions, such as by hydrogenation using a suitablecatalyst or using a suitable reducing agent.

For example, an appropriate amine of formula (1) is contacted with anappropriate aldehyde of formula (2) (or alternately an appropriate amineof formula (4) and an appropriate aldehyde of formula (3)) and asuitable reducing agent to give a compound of formula I. The reaction iscarried out in a suitable solvent, such as methanol, ethanol,tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran,dichloromethane, and 1,2-dichloroethane. The reaction may be carried outin the presence of a drying agent, such as sodium sulfate, cupricsulfate, or molecular sieves. The reaction is carried out in thepresence of from about 1 to 20 molar equivalents of a suitable reducingagent, such as, sodium borohydride, sodium cyanoborohydride, and sodiumtriacetoxyborohydride. It may be advantageous to allow Schiff baseformation to proceed before addition of the suitable reducing agent.When sodium cyanoborohydride is used it may be advantageous to monitorand adjust the pH during the course of the reaction as is known in theart. The reaction is generally carried out at temperatures of from 0° C.to the refluxing temperature of the solvent. Generally, the reactionsrequire 1 to 72 hours. The product can be isolated and purified bytechniques well known in the art, such as filtration, extraction,evaporation, trituration, chromatography, and recrystallization. SchemeA, optional step b, not shown, an acid addition salt of a compound offormula I is formed using a pharmaceutically-acceptable acid. Theformation of acid addition salts is well known and appreciated in theart.

Scheme B depicts alternative methods for the preparation of compounds offormula I by formation and reduction of an amide.

In one alternative, Scheme B, step a, depicts contacting an appropriatecompound of formula (1) with an appropriate compound of formula (5) in aamide forming reaction to give a compound of formula (6). An appropriatecompound of formula (1) is as described in Scheme A. An appropriatecompound of formula (5) is one in which A is an activating group, takingthe form of an acid halide, activated ester, activated amide, oranhydride, and X, R₃, and R₄ are as desired in the final product offormula I, or give rise to groups desired in the final product offormula I.

In another alternative, Scheme B, step a, depicts contacting anappropriate compound of formula (7) with an appropriate compound offormula (4) in a amide forming reaction to give a compound of formula(8). An appropriate compound of formula (7) is one in which A is anactivating group as described above and R₁ is as desired in the finalproduct of formula I. An appropriate compound of formula (4) is asdescribed in Scheme A. Appropriate compounds of formula (4) and (7) aregenerally available from commercial sources and can also be prepared bymethods described herein and by methods described in the art.

The amide formation reaction depicted in Scheme B, step a, is readilyaccomplished by a number of methods readily available to the skilledperson, including those which are conventionally conducted for peptidesynthesis. Such methods can be carried out on the acid, acid halide,activated esters, activated amides, and anhydrides.

For example, well known coupling reagents such as a carbodiimides withor without the use of well known additives such as N-hydroxysuccinimide,1-hydroxybenzotriazole, etc. can be used to facilitate amide formation.Such coupling reactions are typically use about 1 to 1.5 molar ratios ofacid, amine, and coupling reagent and are conventionally conducted in aninert aprotic solvent such as pyridine, dimethylfomamide,dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile,tetrahydrofuran and the like. It may be advantageous to use a suitablebase, such as triethylamine or N,N-diisopropylethylamine, in suchcoupling reactions. The reaction is preferably conducted at from about0° C. to about 60° C. until reaction completion which typically occurswithin 1 to about 48 hours. Upon reaction completion, the product can beisolated and purified by techniques well known in the art, such asfiltration, extraction, evaporation, trituration, chromatography, andrecrystallization.

Alternatively, for example, an acid halide can be employed in thereaction. It may be advantageous to use a suitable base to scavenge theacid generated during the reaction, suitable bases include, by way ofexample, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine,pyridine, and the like. Typically, about 1 to 1.5 molar ratios of theacid halide and amine are used. The reaction can be carried out in avariety of inert aprotic solvents such as pyridine, dichloromethane,chloroform, 1,2-dichloroethane, tetrahydrofuran, and the like. Thereaction is preferably conducted at from about 0° C. to about 60° C.until reaction completion which typically occurs within 1 to about 12hours. Upon reaction completion, the product can be isolated andpurified by techniques well known in the art, such as filtration,extraction, evaporation, trituration, chromatography, andrecrystallization.

Alternatively, for example, an acid halide can be employed in thereaction under Schotten-Baumann conditions. Typically, under suchconditions 1 to 10 molar equivalents of amine are used. Such couplingsgenerally use a suitable base to scavenge the acid generated during thereaction, such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, and the like. The reaction can be carried out in a varietyof mixed solvent systems such as dichloromethane, chloroform, ethylacetate, tetrahydrofuran and the like; and water. The reaction ispreferably conducted at from about 0° C. to about 80° C. until reactioncompletion which typically occurs within 1 to about 6 hours. Uponreaction completion, the product can be isolated and purified bytechniques well known in the art, such as filtration, extraction,evaporation, trituration, chromatography, and recrystallization.

Alternatively, for example, an anhydride (either symmetrical or mixed)can be employed in the reaction. Such anhydrides are formed by numerousmethods known in art. Typically, about 1 to 1.5 molar equivalents of theanhydride and amine are used. It may be advantageous to use a suitablebase to scavenge the acid generated during the reaction. Suitable basesinclude, by way of example, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate,sodium bicarbonate, and the like. The reaction can be carried out in avariety of solvents. The reaction is preferably conducted at from about0° C. to about 60° C. until reaction completion which typically occurswithin 1 to about 12 hours. Upon completion, the product can be isolatedand purified by techniques well known in the art, such as filtration,extraction, evaporation, trituration, chromatography, andrecrystallization.

Scheme B, steps b, depicts reduction of a compound of formula (6) or (8)to give a compound of formula I.

For example, a compound of formula (6) or (8) is contacted with asuitable reducing agent to give a compound of formula I. Suitablereducing agents are those which are capable of reducing an amide to anamine and include, borane reagents, such as borane dimethyl sulfidecomplex, hydride transfer reagents, such as aluminum hydride and lithiumaluminum hydride, and the like. The reaction is carried out in asolvent, such as tetrahydrofuran or diethyl ether, typically using 1 to10 equivalents of reducing agent. The reaction is generally conducted atfrom about 0° C. the refluxing temperature of the selected solvent andtypically occurs within 1 to about 48 hours. The product can be isolatedand purified by techniques well known in the art, such as quenching,filtration, extraction, evaporation, trituration, chromatography, andrecrystallization.

Scheme B, as an optional step, not shown, an acid addition salt of acompound of formula I is formed using a pharmaceutically-acceptableacid. The formation of acid addition salts is well known and appreciatedin the art.

In Schemes A and B, as an optional step, not shown, as will beappreciated by the skilled person, a compound of formula I in which R₂is hydrogen can be alkylated to give a compound in which R₂ is nothydrogen. Methods for alkylating such secondary amines are will known inthe art and discussed in Scheme C, step c, below.

In Schemes A and B, as will be appreciated by the skilled person,compounds of formula II are also prepared by the methods described inSchemes A and B using compounds of the formula (9) and (10), below:

An appropriate compound of formula (9) is one in which Y, R₅ and R₆ areas desired in the final product of formula II and an appropriatecompound of formula (10) is one in which A is an activating group, asdescribed above, and Y, R₅ and R₆ are as desired in the final product offormula II.

Starting material for Schemes A and B are prepared in the Schemes below.In the Schemes below all substituents, unless otherwise indicated, areas previously defined, and all starting material and reagents are wellknown and appreciated in the art.

Scheme C describes methods for preparing compounds of formula (1).

Scheme C, step a, depicts the reaction of an appropriate aldehyde offormula (24) and nitromethane to give the compound of formula (25). Anappropriate aldehyde of formula (24) is one in which R₁ is as desired inthe final product of formula I. The reaction of the anion ofnitromethane with aldehydes to give nitro olefins is well known andappreciated in the art. Modern Synthetic Reactions, H. O. House (2nd ed.The Benjamin/Cummings Publishing Company 1972).

For example, an appropriate aldehyde of formula (24) is condensed withnitromethane to give the compound of formula (25). Typically thereaction is carried out in the presence of an excess of nitromethane.The reaction is performed in a suitable solvent, such astetrahydrofuran, nitromethane, and dimethyl sulfoxide. The reaction isperformed using from about 1.1 to about 3 molar equivalents of asuitable base, such as sodium bis(trimethylsilyl)amide, potassiumt-butoxide, sodium hydride, sodium acetate, triethylamine,N,N-diisopropylethylamine, ammonium salts, such as ammonium acetate. Thereaction is carried out at temperatures of from about −20° C. to thereflux temperature of the selected solvent and generally require from 6hours to 48 hours. The product of the coupling reaction can be isolatedand purified using techniques well known in the art, includingextraction, evaporation, chromatography and recrystallization.

Scheme C, step b, depicts the reduction of a compound of formula (25) togive a compound of formula (1) in which R₂ is hydrogen.

For example, an appropriate compound of formula (25) is hydrogenatedover a suitable catalyst, such as Raney® nickel or a palladium catalyst.When Raney nickel is used, the reaction is carried out in a suitablesolvent, such as ethanol, methanol, water, and mixtures thereof. It maybe advantageous to carry out the hydrogenation under acidic conditions,for example, using hydrochloric or sulfuric acid. When a palladiumcatalyst is used palladium-on-carbon is preferred and the reaction iscarried out in a suitable solvent, such as ethanol, methanol,tetrahydrofuran, water, and mixtures thereof. It may be advantageous tocarry out the hydrogenation under acidic conditions, for example, usinghydrochloric, trifluoroacetic acid, or sulfuric acid. The reaction isgenerally carried out at temperatures of from ambient temperature to 70°C. The reaction is carried out with hydrogen at pressures of from 15 psito 120 psi in an apparatus designed for carrying out reactions underpressure, such as a Parr® hydrogenation apparatus. The product can beisolated by carefully removing the catalyst by filtration andevaporation. The product can be purified by extraction, evaporation,trituration, chromatography, and recrystallization.

Alternately, for example, an appropriate compound of formula (25) iscontacted with a suitable reducing agent. Suitable reducing agentsinclude hydride transfer reagents, such as aluminum hydride and lithiumaluminum hydride, and the like. The reaction is carried out in asolvent, such as tetrahydrofuran or diethyl ether, typically using 1 to10 equivalents of reducing agent. The reaction is generally conducted atfrom about 0° C. the refluxing temperature of the selected solvent andtypically occurs within 1 to about 48 hours. The product can be isolatedand purified by techniques well known in the art, such as quenching,filtration, extraction, evaporation, trituration, chromatography, andrecrystallization.

Additionally, an appropriate compound of formula (25) can be reduced intwo steps to a compound of formula (1). For example, the vinyl group ofa compound of formula (25) can be reduced using reagents such as sodiumborohydride. The reaction is typically carried out using an excess ofborohydride in a solvent, such as methanol, ethanol, isopropanol, water,and the like. The intermediate 2-nitroethyl compound can be isolated andpurified by techniques well known in the art, such as quenching,filtration, extraction, evaporation, trituration, chromatography, andrecrystallization. The intermediate 2-nitroethyl compound can then bereduced using a variety of methods, such as the hydrogenation andhydride transfer reagents as discussed above. Also, the intermediate2-nitroethyl compound can be reduced using metals such as zinc to givethe desired anine of formula (1) in which R₂ is hydrogen.

Scheme C, step c, depicts the optional alkylation of a compound offormula (1) in which R₂ is hydrogen to give a compound of formula (1) inwhich R₂ is not hydrogen.

For example, a compound of formula (1) in which R₂ is hydrogen iscontacted with a suitable alkylating agent. A suitable alkylating agentis one which transfers a group R₂ as is desired in the final product offormula I. Suitable alkylating agents include C₁-C₃ alkyl halides. Thereaction is carried out in a suitable solvent, such as dioxane,tetrahydrofuran, tetrahydrofuran/water mixtures, or acetonitrile. Thereaction is carried out in the presence of from 1.0 to 6.0 molarequivalents of a suitable base, such as sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, triethylamine,or N,N-diisopropylethylamine. The reaction is generally carried out attemperatures of from −78° C. to the refluxing temperature of thesolvent. Generally, the reactions require 1 to 72 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

Alternately, for example, a compound of formula (1) in which R₂ ishydrogen undergoes a reductive amination with an aldehyde or ketonewhich gives a compound of formula (1) in which R₂ is not hydrogen.Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde,and acetone. The reaction is carried out as described in Scheme A, stepa.

In another alternate, for example, a compound of formula (1) in which R₂is hydrogen undergoes amide or carbamate formation followed by reductionto give a compound of formula (1) in which R₂ is not hydrogen. Suitablealdehydes include formaldehyde, acetaldehyde, propionaldehyde, andacetone. The reaction is carried out as described in Scheme A, step a.

Scheme C, steps d and e, depict an alternative approach to preparing thecompounds of formula (1) via formation of an amide using an appropriatecompound of formula (7) and an appropriate amine of formula (26) to givean amide of formula (27), followed by reduction to give a compound offormula (1). An appropriate compound of formula (7) is as described inScheme B. An appropriate amine of formula (26) is one which gives R₂ asdesired in final compound of formula I. The skilled person willrecognize that many of the amides of formula (27) are commerciallyavailable and available in the art.

The amide formation and reduction in Scheme C are carried out asdescribed in the Scheme B.

Scheme D describes methods for preparing compounds of formula (1) inwhich R₁ is optionally substituted indol-3-yl.

Scheme D, step a, depicts the two-step reaction of an appropriate indoleof formula (28) with oxalyl chloride followed by an appropriate amine offormula (26), R₂NH₂ to give a compound of formula (29). An appropriateindole of formula (28) is one in which Z′ represents optionalsubstituents on the indole 2- and 4- to 7-positions as desired in thefinal product of formula I. An appropriate amine of formula (26) is asdescribed in Scheme C, above.

For example, an appropriate indole of formula (28) is contacted withabout 1 to 2 molar equivalents of oxalyl chloride to give anintermediate keto-acid chloride. The reaction is carried out in asuitable solvent, such a diethyl ether or tetrahydrofuran. The reactionis generally carried out at temperatures of from 0° C. to 40° C. andgenerally require from 6 hours to 48 hours. The intermediate keto-acidchloride product can be isolated and purified using techniques wellknown in the art, including extraction, evaporation, chromatography andrecrystallization. Generally, the intermediate keto-acid chlorideproduct is used directly after isolation. The intermediate keto-acidchloride product is contacted with an appropriate amine, R₂NH₂, asdefined above and using the procedures described above.

Scheme D, step b, depicts the reduction of a compound of formula (29) togive a compound of formula (1) in which R₁ is optionally substitutedindol-3-yl.

For example, a compound of formula (29) is reduced using a suitablereducing reagent such as, lithium aluminum hydride to give a compound offormula (1) which R₁ is optionally substituted indol-3-yl. The reactionis carried out in a solvent, such as tetrahydrofuran or diethyl ether,typically using 1 to 12 molar equivalents of reducing agent. Thereaction is generally conducted at from about 0° C. the refluxingtemperature of the selected solvent and typically occurs within 12 toabout 48 hours. The product can be isolated and purified by techniqueswell known in the art, such as quenching, filtration, extraction,evaporation, trituration, chromatography, and recrystallization.

In Scheme D, step c, an appropriate indole of formula (28) is formylatedto give a compound of formula (30). An appropriate indole of formula(28) is as described in step a, above.

For example, an appropriate indole of formula (28) is reacted with asuitable formyl transfer reagent, such as the Vilsmeier reagent formedfrom dimethylformamide. Generally, about 1 molar equivalent of formyltransfer reagent is used. The reaction is performed in a suitablesolvent, such as benzene, dimethylformamide, tetrahydrofuran, or diethylether. The reaction is carried out at temperature of from about −70° C.to about 20° C. and generally require from 1 hours to 6 hours. Theproduct of the reaction can be isolated and purified using techniqueswell known in the art. These techniques include extraction, evaporation,chromatography and recrystallization.

In Scheme D, step d, an appropriate indole of formula (28) is contactedwith (CH₃)₂N—CH═CH—NO₂ to give a compound of formula (30). Anappropriate indole of formula (28) is as described in step a, above.

For example, an appropriate indole of formula (28) is reacted with1-dimethylamino-2-nitroethylene. Generally, about 1 equimolar amounts ofreagents. The reaction is performed in a suitable solvent, such astrifluoroacetic acid or dichloromethane containing about 2 to 15equivalents of trifluoroacetic acid. The reaction is carried out attemperature of from about −70° C. to about 20° C. and generally requirefrom 1 hours to 24 hours. The product of the reaction can be isolatedand purified using techniques well known in the art. These techniquesinclude extraction, evaporation, chromatography and recrystallization.

Scheme D, steps e and f, depict an the reaction of an aldehyde offormula (30) to give a nitro olefin of formula (31) and the reduction ofthe nitro olefin to give a compound of formula (1) in which R₁ isoptionally substituted indol-3-yl. These steps can be carried out usingthe methods described in Scheme C.

As will be appreciated by the skilled person, in steps not shown, theindole nitrogen of a compound of formula (1) can be substituted, asdesired, using suitable amine protecting groups to give compounds inwhich R₁ is 1-substituted indol-3-yl. Also as will be appreciated by theskilled person, in steps described in Scheme C, R₂ groups which are nothydrogen can be introduced by various methods.

Scheme E describes methods for preparing compounds of formula (2) inwhich X is —O— or —S—.

Scheme E, step a, depicts the formation of an acetal of an appropriatecompound of formula (11) to give a compound of formula (12). Anappropriate compound of formula (11) is one in which X and R₃ are asdesired in the final compound of formula I. Such acetal formationreactions are readily accomplished by methods well known in the art.(Protecting Groups in Organic Synthesis, Theodora Greene(Wiley-Interscience)).

For example, a compound formula (11) is contacted under acid catalysiswith an appropriate alcohol, HOR. An appropriate alcohol is one whichgives an acetal with is stable to the reaction in step b and can beremoved in step c to give a compound of formula (2). Appropriatealcohols include methanol, ethanol, propanol, 1,3-propane diol, ethyleneglycol, and the like.

In Scheme E, step b, an appropriate compound of formula (11), (12), or(14) is reacted with an R₄ group transfer reagent, as desired, to give acompound of formula (2), (13), or (15); respectively. Appropriatecompounds of formula (11), (12), and (14) are ones in which X and R₃ areas desired in the final product of formula 1. A variety of reagents thattransfers an R₄ as desired in the final product are available andsuitable for the reaction depicted in Scheme E. Such reagents includehalopyridines, halopryidine N-oxides, allyl halides, C₂-C₄ alkanols,C₂-C₄ alkyl halides and sulfonates, fluorinated C₂-C₄ alkanols,fluorinated C₂-C₄ alkyl halides and sulfonates, optionally substitutedphenyl having at least one fluoro or chloro atom, optionally substitutedphenylsulfonyl halides or anhydrides, and optionally substituted benzylhalides.

For example, where the appropriate R₄ group transfer reagent is ahalide, sulfonate, or anhydride, an appropriate compound of formula(11), (12), or (14) is coupled under basic conditions to give a compoundof formula (2), (13), or (15); respectively. The reaction is performedin a suitable solvent, such as acetonitrile, dimethylformamide,dimethylacetamide, tetrahydrofuran, pyridine, and dimethyl sulfoxide.The reaction is carried out in the presence of from about 1 to about 3molar equivalents of a suitable base, such as potassium hydride, sodiumhydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesiumcarbonate, N,N-diisopropylethylamine, triethylamine, and the like. Thereaction is carried out at temperature of from about −30° C. to about100° C. and generally require from 6 hours to 48 hours. The product ofthe reaction can be isolated and purified using techniques well known inthe art. These techniques include extraction, evaporation,chromatography and recrystallization.

Of course, when a halopyridine N-oxide is used the N-oxide is remove byreduction to give the R₄ as desired in the final product of formula I.Such reductions are readily accomplished by the skilled person, andinclude catalytic reduction over palladium catalysts using hydrogen orammonium formate in a suitable solvent such as methanol, ethanol, water,and mixtures thereof.

Alternately, for example, where the appropriate R₄ group transferreagent is an alkanol, the coupling can be carried out under Mitsunobuconditions which are well known in the art. The reaction is carried outin a suitable solvent, such as tetrahydrofuran and diethyl ether using aphosphine, such as triphenylphosphine or a resin bound phosphine and adialkyl azodicarboxylate, such as diethyl azodicarboxylate, diisopropylazodicarboxylate or di-t-butyl azodicarboxylate. The reaction isgenerally carried out at temperatures of from ambient temperatures to60° C. The reaction generally requires from 1 hour to 12 hours. Theproduct can be isolated by techniques well known in the art, such asextraction and evaporation. The product can then be purified bytechniques well known in the art, such as distillation, chromatography,or recrystallization.

Scheme E, step c, depicts the deprotection of an acetal of formula (13)to give a compound of formula (2). Such deprotections are readilyaccomplished by methods well known in the art. (Protecting Groups inOrganic Synthesis, Theodora Greene (Wiley-Interscience)).

For example, a compound formula (13) is contacted under acid underaqueous conditions to give a compound of formula (2).

In Scheme E, step d, a bromo compound of formula (15) is formylated togive a compound of formula (2).

For example, a compound of formula (15) is metalated by treatment with ametalation reagent such as butyl lithium. The reaction is performed in asuitable solvent, such as hexane, benzene, toluene, tetrahydrofuran ordiethyl ether. The reaction is typically carried out in the presence offrom about 1 to about 1.5 molar equivalents of a metalating reagent. Themetalation reaction is cared out at temperature of from about −70° C. toabout 20° C. and generally require from 1 hours to 6 hours. Themetalated species is then treated with a formyl transfer reagent, suchas dimethylformamide or an alkyl chloroformate to give a compound offormula (2) or a alkoxycarbonyl compound which can be elaborated to analdehyde as described herein. The product of the reaction can beisolated and purified using techniques well known in the art. Thesetechniques include extraction, evaporation, chromatography andrecrystallization.

Scheme F describes methods for preparing compounds of formula (2) fromthe versatile intermediate, compound (17), which readily prepared byacetal formation as described above.

Scheme F, step a, depicts an aromatic displacement reaction of anappropriate compound of formula (17) and an appropriate alcohol (R₄OH)or an appropriate thiol (R₄SH) to give a compound of formula (13) inwhich X is —O— or —S— are defined above in Scheme E. An appropriatecompound of formula (17) is one in which R₃ is as desired in the finalproduct of formula I. In an appropriate alcohol (R₄OH) or an appropriatethiol (R₄SH), R₄ is as desired in the final product of formula J, andincludes C₂-C₄ alkyl alcohols and thiols, fluorinated C₂-C₄ alkylalcohols and thiols, optionally substituted phenols and thiophenols,optionally substituted benzyl alcohols and thiols.

For example, an appropriate compound of formula (17) and an appropriatealcohol (R₄OH) or an appropriate thiol (R₄SH) are coupled give acompound of formula (13). The reaction is performed in a suitablesolvent, such as dimethylformamide, dimethylacetamide, and dimethylsulfoxide. The reaction is performed using from about 1.1 to about 3molar equivalents of an appropriate alcohol or thiol. The reaction iscarried out in the presence of from about 1 to about 6 molar equivalentsof a suitable base, such as potassium hydride, sodium hydroxide,potassium carbonate, sodium carbonate, or sodium hydride. The couplingis performed using a suitable catalyst, such as copper salts. Thereaction generally requires from 6 hours to 48 hours. The product of thecoupling reaction can be isolated and purified using techniques wellknown in the art. These techniques include extraction, evaporation,chromatography and recrystallization.

Scheme F, steps b-e, depict a number of reactions of an appropriatecompound of formula (17), after metalation as described in Scheme E,step d, to give compounds of formula (18)-(21), respectively. In thesesteps an appropriate compound of formula (17) is one in which R₃ is asdesired in the final product of formula I and is not adversely affectedby the metalation conditions of the reaction. Generally, these reactionsare performed in the solvent used and at the temperature used to formthe metalated species. The products of these reactions can be isolatedand purified using techniques well known in the art, include quenching,extraction, evaporation, trituration, chromatography, andrecrystallization.

For example, in Scheme F, step b, a metalated compound of formula (17)is contacted with an appropriate disulfide (R₄S—)₂, to give a compoundof formula (18). An appropriate disulfide is one that gives R₄ asdesired in the final product of formula I and gives rise to compounds inwhich X is —S—. Appropriate disulfides include C₁-C₄ alkyl disulfides,optionally substituted phenyl disulfides, and optionally substitutedbenzyl disulfides. The reaction is performed using from about 1 to about2 molar equivalents of an appropriate disulfide. The reaction istypically carried out in the same solvent used for the metallation andat temperatures of about −78° C. to about 50° C. The reaction generallyrequire from 12 hours to 48 hours.

For example, in Scheme F, step c, a metalated compound of formula (17)is contacted with an appropriate sulfonyl fluoride (R₄SO₂F) to give acompound of formula (19). An appropriate sulfonyl fluoride is one thattransfers R₄ as desired in the final product of formula I and gives riseto compounds in which X is —SO₂—. Appropriate sulfonyl fluorides includean optionally substituted phenyl sulfonyl fluoride. The reaction isperformed using from about 1 to about 3 molar equivalents of anappropriate sulfonyl fluoride. The reaction is typically carried out inthe same solvent used for the metallation and at temperatures of about−78° C. to about 0° C. The reaction generally require from 2 hours to 12hours.

For example, in Scheme F, step d, a metalated compound of formula (17)is contacted with an appropriate acid chloride (R₄C(O)Cl) to give acompound of formula (20). An appropriate acid chloride is one thattransfers R₄ as desired in the final product of formula I and gives riseto compounds in which X is —C(O)—. Appropriate acid chlorides includeC₂-C₄ alkyl acid chlorides, fluorinated C₂-C₄ allyl acid chlorides,optionally substituted phenyl acid chlorides, optionally substitutedbenzyl acid chlorides, and optionally substituted 5 to 6 memberedmonocyclic aromatic heterocycle acid chlorides. The reaction isperformed using from about 0.8 to about 1.2 molar equivalents of anappropriate acid chloride. The reaction is typically carried out in thesame solvent used for the metallation and at temperatures of about −78°C. to about 50° C. The reaction generally require from 1 hours to 12hours.

For example, in Scheme F, step e, a metalated compound of formula (17)is contacted with an appropriate aldehyde (R₄C(O)H) to give a compoundof formula (21). An appropriate aldehyde is one that transfers R₄ asdesired in the final product of formula I and gives rise to compounds inwhich X is —CH(OH)—. Appropriate aldehydes include C₂-C₄ alkyl aldehyde,fluorinated C₂-C₄ alkyl aldehyde, optionally substituted phenylaldehyde, optionally substituted benzyl aldehyde, and optionallysubstituted 5 to 6 membered monocyclic aromatic heterocycle aldehyde.The reaction is performed using from about 1 to about 3 molarequivalents of an appropriate aldehyde. The reaction is typicallycarried out in the same solvent used for the metallation and attemperatures of about −50° C. to about 50° C. The reaction generallyrequires from 4 hours to 24 hours.

As will be appreciate by the skilled person, compounds of formula(18)-(21) can undergo a number of other transformations which aredepicted in Scheme F, steps f-i, to give, ultimately, compounds offormula I having various groups at X. These transformations are trivialand well within the ability of the skilled person. These transformationsinclude oxidation of sulfides (step f) which can be accomplished byperoxide, peracids, and other reagents known in the art; reduction of abenzyl alcohol (step g) which can be accomplished by a variety ofreagents, such as triethylsilane/trifluoroacetic acid; halogenation of abenzyl alcohol to give fluoro (step h) using reagents such as DAST andfluorinating reagents; reduction of a ketone (step i) using varioushydride transfer reagents or oxidation of a benzylic alcohol (step i)which can be accomplished by manganese dioxide or Swern conditions.

In Scheme F, step j, compounds of the formula (13) and (18)-(23) aredeprotected to give an aldehyde of formula (2) as described in Scheme E,step c.

Scheme G describes methods for preparing compounds of formula (5).

Scheme G, step a, a bromo compound of formula (15) is carboxylated togive a compound of formula (5) in which A is —OH.

For example, a compound of formula (15) is metalated as described inScheme E, step d, and the metalated species is then treated with carbondioxide to give a compound of formula (5) in which A is —OH. The productof the reaction can be isolated and purified using techniques well knownin the art. These techniques include extraction, evaporation,chromatography and recrystallization.

Scheme G, step b, a bromo compound of formula (15) is alkoxyformylatedusing an appropriate chloroformate or carbonate to give a compound offormula (32). An appropriate chloroformate or carbonate is one thattransfers an RO(O)C— group in which R is methyl, ethyl, or benzyl.

For example, a compound of formula (15) is metalated as described inScheme E, step d, and the metalated species is then treated with about 1to 3 molar equivalents of an appropriate chloroformate or carbonate. Thereaction is typically carried out in the same solvent used for themetallation and at temperatures of about −78° C. to about 50° C. Thereaction typically requires from 1 to 24 hours. The product of thereaction can be isolated and purified using techniques well known in theart. These techniques include extraction, evaporation, chromatographyand recrystallization.

In Scheme G, step c, an appropriate compound of formula (33) is reactedwith an R₄ group transfer reagent, as desired, to give a compound offormula (32). An appropriate compound of formula (33) is one in which Xand R₃ are as desired in the final product of formula I. Reagents thattransfers an R₄ are as described in Scheme E.

For example, where the appropriate R₄ group transfer reagent is a halideor anhydride, an appropriate compound of formula (34) is coupled underbasic conditions with to give a compound of formula (33). The reactionis performed in a suitable solvent, such as dimethylformamide,tetrahydrofuran, or pyridine. The reaction is typically carried out inthe presence of from about 1 to about 3 molar equivalents of a suitablebase, such as sodium carbonate, potassium carbonate, cesium carbonate,N,N-diisopropylethylamine, triethylamine, and the like. The reaction iscarried out at temperature of from about −30° C. to about 100° C. andgenerally require from 6 hours to 48 hours. The product of the reactioncan be isolated and purified using techniques well known in the art.These techniques include extraction, evaporation, chromatography andrecrystallization.

Alternately, for example, where the appropriate R₄ group transferreagent is an alkanol, the coupling can be carried out under Mitsunobuconditions which are well known in the art and described in Scheme E.

Scheme G, step d, an ester of formula (32) is deprotected to give acompound of formula (5) in which A is —OH. Such deprotections arereadily accomplished by methods well known in the art. (ProtectingGroups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).

Scheme G, step e, a compound of formula (5) in which A is —OH isconverted to a compound of formula (5) in which A is an activatinggroup, such as acid halide, activated ester, activated amide, oranhydride. The formation of such activated intermediates is well knownand appreciated in the art.

For example, an acid halide can be prepared by a variety of reagent suchas oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide,phosphorous oxychloride, phosphorous trichloride, and phosphorouspentachloride; a mixed anhydride of substituted phosphoric acid, such asdialkylphosphoric acid, diphenylphosphoric acid, halophosphoric acid; ofaliphatic carboxylic acid, such as formic acid, acetic acid, propionicacid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid;an activated ester, such as phenol ester, p-nitrophenol ester,N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,1-hydroxybenztriazole ester, or activated amide, such as imidazole,dimethylpyrazole, triazole; are prepared by method which are well knownand appreciated in the art. Such activated intermediates may be preparedand used directly or are prepared and isolated before use in the schemesabove.

Scheme H describes methods for preparing compounds of formula (4).

Scheme H, step a, a bromo compound of formula (15) is converted to anitrile of formula (35).

For example, a compound of formula (15) is treated with copper (I)cyanide to give a compound of formula (35). The reaction is performed ina suitable solvent, such as dimethylformamide. The reaction is typicallycarried out in the presence of from about 1 to about 3 molar equivalentsof copper (I) cyanide. The reaction is carried out at temperature offrom about ambient temperature to about 100° C. and generally requirefrom 6 hours to 48 hours. The product of the reaction can be isolatedand purified using techniques well known in the art. These techniquesinclude extraction, evaporation, chromatography and recrystallization.

Scheme H, step b, a nitrile compound of formula (35) reduced to give acompound formula (4) in which R₂ is hydrogen.

For example, a nitrile compound of formula (35) is contacted with sodiumborohydride in the presence of cobalt chloride. The reaction is carriedout in a suitable solvent, such as methanol, or ethanol. The reaction isgenerally carried out at temperatures of from 0° C. to 50° C. Generally,the reactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction withaqueous acid, evaporation, trituration, chromatography, andrecrystallization.

Alternately, for example, a nitrile compound of formula (35) ishydrogenated over a suitable catalyst, such as Raney® nickel. Thereaction is carried out in a suitable solvent, when Raney® nickel isused as the catalyst, suitable solvents will generally contain ammonia,such as ethanol/ammonium hydroxide. The reaction is generally carriedout at temperatures of from ambient temperature to 50° C. The reactionis carried out at pressures of from 15 psi (103 kPa) to 120 psi (827kPa) in an apparatus designed for carrying out reactions under pressure,such as a Parr hydrogenation apparatus. The product can be isolated bycarefully removing the catalyst by filtration and evaporation. Theproduct can be purified by extraction, evaporation, trituration,chromatography, and recrystallization.

Scheme H, step c, a nitrile compound of formula (35) is converted to aamide of formula (36).

For example, a compound of formula (35) is treated with acid or baseunder hydrolysis conditions to give a compound of formula (36). Thereaction is performed in a suitable solvent, such as ethanol,isopropanol, dimethylsulfoxide, each containing water. The hydrolysis ofan aromatic nitrile to an amide is well known and appreciated in theart. The product of the reaction can be isolated and purified usingtechniques well known in the art. These techniques include extraction,evaporation, chromatography and recrystallization.

Scheme H, step d, depicts formation of an amide of formula (37) byreacting a compound of formula (5) and an appropriate amine of formulaH₂NR₂ in a amide forming reaction. An appropriate amine of formula H₂NR₂is one which gives R₂ as desired in the final product of formula I.Suitable methods of forming amides are well known in the art and aredescribed in Scheme B, above.

Scheme H, step e, a amide compound of formula (36) or (37) is reduced toa compound of formula (4). Such reductions of amides are readily carriedout as described in Scheme B, above, and as known in the art.

Scheme H, step f, a compound of formula (2) and an appropriate amine offormula H₂NR₂ undergo reductive amination to give a compound of formula(4). Such reductive aminations are readily carried out as described inScheme B, above, and by other methods known in the art.

As will be appreciated by the skilled person, the compounds of formulaII are readily prepared by methods analogous to those described above.

The present invention is further illustrated by the following examplesand preparations. These examples and preparations are illustrative onlyand are not intended to limit the invention in any way.

The terms used in the examples and preparations have their normalmeanings unless otherwise designated. For example, “° C.” refers todegrees Celsius; “N” refers to normal or normality; “M” refers to molaror molarity; “mmol” refers to millimole or millimoles; “g” refers togram or grams; “mL” refers milliliter or milliliters; “mp” refers tomelting point; “brine” refers to a saturated aqueous sodium chloridesolution; etc. In the ¹H NMR, all chemical shifts are given in 6, unlessotherwise indicated.

EXAMPLE 1 2-(3-(4-Fluorophenoxy)phenyl)-(1,3)dioxolane

Combine 4-fluorophenol (3.0 g, 227.8 mmol),2-(3-bromophenyl)-1,3-dioxolane (5.0 ml, 33.3 mmol), potassium carbonate(anhydrous, 8.0 g, 55.6 mmol), and dry pyridine (50 ml). Heat to 90° C.and add copper oxide (5.5 g, 69.5 mmol). Heat at reflux. After 24 hours,cool to room temperature, dilute with dichloromethane, and filter.Concentrate the filtrate in vacuum to give a yellow oil. Chromatographthe oil on silica gel eluting with 95:5 hexane:EtOAc to give the titlecompound.

By the method of Example 1 the following compounds were prepared: a)2-(3-(2-Fluorophenoxy)phenyl)-(1,3)dioxolane;

-   b) 2-(3-(3-Fluorophenoxy)phenyl)-(1,3)dioxolane;-   c) 2-(3-(Naphth-2-yloxy)phenyl)-(1,3)dioxolane;-   d) 2-(3-(Naphth-1-yloxy)phenyl)-(1,3)dioxolane;-   e) 2-(3-(Pyrid-3-yloxy)phenyl)-(1,3)dioxolane;-   f) 3-(Pyridin-3-yloxy)benzaldehyde;-   g) 3-(Pyrimidin-5-yloxy)benzaldehyde; and-   h) 3-(Pyridin-4-yloxy)benzaldehyde.

EXAMPLE 2 3-[1,3]Dioxolan-2-ylphenyl)phenylamine

Combine 2-(3-bromophenyl)-1,3-dioxolane (0.7 ml, 4.3 mmol), aniline (0.4ml, 4.7 mmol), sodium t-butoxide (0.6 g, 6.0 mmol), BINAP (10.0 mg, 0.03mol), Pd₂(dba)₃ (30.0 mg, 0.01 mmol) and toluene (20 ml). Heat at 80° C.After 18 hours, cool to room temperature, dilute with ether (40 ml),filter, and concentrate to give a residue. Chromatograph the residue onsilica gel eluting with 9:1 hexane:EtOAc to give the title compound.

By the method of Example 2 the following compounds were prepared: a)Benzyl-(3-[1,3]dioxolan-2-ylphenyl)-amine;

-   b) (3-[1,3]Dioxolan-2-ylphenyl)-pyridin-3-ylamine;-   c) (3-[1,3]Dioxolan-2-ylphenyl)-pyridin-4-yl amine; and-   d) (3-[1,3]Dioxolan-2-ylphenyl)-pyridin-2-ylamine.

EXAMPLE 3 2-(3-Phenylsulfanylphenyl)-[1,3]-dioxolane

Combine 2-(3-bromophenyl)-1,3-dioxolane (3.0 ml, 20.0 mmol) andtetrahydrofuran (100 ml). Cool to about −78° C. Add dropwise a solutionof n-butyllithium, 1.6 M solution in hexane (13.4 ml, 21.0 mmol). After10 minutes, add phenyl disulfide (4.3 g, 20.0 mmol) as a solution intetrahydrofuran (50 ml). After 1 hour, warm to room temperature over 1hour then quenched with water (150 ml) and extract with ether. Extractthe combined organic layers sequentially with distilled water and brineand then dry (Na₂SO₄), filter, and concentrate to give a residue.Chromatograph the residue eluting with 9:1 hexane:EtOAc gives the titlecompound.

By the method of Example 3 the following compounds were prepared: a)2-(3-p-Tolylsulfanylphenyl)-[1,3]-dioxolane.

EXAMPLE 4 2-(3-Benzenesulfonylphenyl)-[1,3]-dioxolane

Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (1.0 g, 3.6 mmol) anddichloromethane (15 ml). Cool to about −78° C. Add a slurry ofm-chloroperbenzoic acid (2.3 g, 7.2 mmol) in dichloromethane (10 ml).After 30 minutes, warm to room temperature then add a solution 1N ofsodium thiosulfate (20 ml). After 15 minutes, add a solution ofsaturated sodium bicarbonate. Separate the organic layer and extract theaqueous layer with dichloromethane. combine the organic layers and washsequentially with distilled water and brine and then dry (Na₂SO₄),filter, and concentrate to give a residue. Chromatograph the residueeluting with EtOAc to give the title compound.

By the method of Example 4 the following compounds were prepared: a)2-(3-(Toluenesulfonyl)-phenyl)-[1,3]-dioxolane.

EXAMPLE 5 (3-[1,3]Dioxolan-2-ylphenyl)phenylmethanol

Combine 2-(3-bromophenyl)-1,3-dioxolane (10.0 ml, 66.0 mmol) andtetrahydrofuran (100 ml) and cool to about −78° C. Add dropwise asolution of n-butyllithium, 1.6 M solution in hexane (44.0 ml, 66.0mmol). After 10 min, add a solution of benzaldehyde (7.6 ml, 66.0 mmol)in tetrahydrofuran (50 ml) via cannula. After 1 hour, warm to roomtemperature. After 18 hours, quench into water and extract withdichloromethane. Combine the organic layers and wash sequentially withdistilled water and brine and then dry (Na₂SO₄), filter, and concentrateto give a residue. Chromatograph the residue eluting with 7:3hexane:EtOAc to give the title compound.

EXAMPLE 6 (3-[1,3]Dioxolan-2-ylphenyl)phenylmethanone

Combine (3-[1,3]dioxolan-2-ylphenyl)-phenyl-methanol (5.0 g, 18.5 mmol)and 18-crown-6 (160 mg, 0.6 mmol) in dichloromethane. Add potassiumpermanganate (8.8 g, 55.5 mmol). Heat to about 40° C. After 4 hours,cool to room temperature add water and sodium hydrogensulfite (6.0 g).Basify with a solution of 1N sodium hydroxide (about 60 ml) and extractwith dichloromethane. Combine the organic layers and wash sequentiallywith distilled water and brine and then dry (Na₂SO₄), filter, andconcentrate to give a residue. Chromatograph the residue eluting withEtOAc to give the title compound.

EXAMPLE 7 3-Benzylbenzaldehyde

Combine (3-[1,3]dioxolan-2-ylphenyl)-phenyl-methanol (2.3 g, 8.7 mmol)and sodium iodide (5.3 g, 35.0 mmol) in acetonitrile (25 ml). Adddichloromethylsilane (2.1 ml, 17.4 mmol) via syringe. After 10 min,dilute with EtOAc and wash with water, saturated sodium bicarbonate, 10%sodium thiosulfate, and then brine. Dry the organic layers (Na₂SO₄),filter, and concentrate to give a residue. Chromatograph the residueeluting with 9:1 hexane:EtOAc to give the title compound.

EXAMPLE 8 2-(3-(α-Fluorobenzyl)phenyl)-[1,3]-dioxolane

Combine (3-[1,3]-dioxolan-2-ylphenyl)phenylmethanol (2.3 g, 8.9 mmol)and dichloromethane (50 ml). Cool to about −78° C. Add dropwise asolution of (diethylamino)sulfur trifluoride (1.7 ml, 12.9 mmol). After10 minutes, quench with water and extract with dichloromethane. Combinethe organic layers and wash sequentially with distilled water and brineand then dry (Na₂SO₄), filter, and concentrate to give a residue.Chromatograph the residue eluting with 7:3 hexane:EtOAc to give thetitle compound.

EXAMPLE 9 3-Nitrodibenzofuran

Combine dibenzofurane (20.0 g, 0.11 mol) and acetic acid (80 ml). Heatto 65° C. Add 98% nitric acid (20.0 g, 11.8 mol). After 3 hours, cool toroom temperature to give a solid. Collect the solid by filtration, rinsewith water, and dry to give the title compound.

EXAMPLE 10 N-Dibenzofuran-3-ylamine

Combine 3-nitrodibenzofuran (22.0 g, 0.1 mol) and Raney nickel (2.75 g),and ethanol (365 ml) and hydrogenate at room temperature and 40 psi (276kPa). After 18 hours, filter and concentrate the filtrate to residue.Chromatograph the residue eluting with 9:1 hexane:EtOAc to give thetitle compound.

EXAMPLE 11 3-Bromodibenzofuran

Combine N-dibenzofuran-3-ylamine (2.0 g, 10.8 mmol), water (20 ml), andconc. hydrobromic acid (6 ml). Cool to 0° C. Add a solution of sodiumnitrite (0.7 g, 10.8 mmol) in water (16 ml). After 15 minutes add themixture above to a mixture of copper bromide (1.7 g, 12.3 mmol) in water(9.2 ml) and hydrobromic acid (4 ml). Warm to ambient temperature. After18 hours, add water and extract with dichloromethane. Combine theorganic layers and wash sequentially with distilled water and brine andthen dry (Na₂SO₄), filter, and concentrate to give a residue.Chromatograph the residue eluting with 8:2 hexane:EtOAc to give thetitle compound.

EXAMPLE 12 Dibenzofuran-3-carbaldehyde

Combine 3-bromodibenzofuran (0.5 g, 2.0 mmol) and tetrahydrofuran (30ml). Cool to about −78° C. Add a solution of t-butyllithium, 1.6 Msolution in hexane (2.2 ml, 3.0 mmol), then warn to about 0° C. for 10min. Cool to about −78° C. and add dimethylformamide (0.5 ml, 5.9 mmol).Warm to room temperature, quench with water, and extract withdichloromethane. Combine the organic layers and wash sequentially withdistilled water and brine and then dry (Na₂SO₄), filter, and concentrateto give a residue. Chromatograph the residue eluting with 8:2hexane:EtOAc to give the title compound.

EXAMPLE 13 3-(Thiazol-2-yloxy)benzaldehyde

In a sealed tube, combine 2-bromo-thiazole (2.0 ml, 22.2 mmol),3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium carbonate (2.1g, 15.0 mmol) in dimethylformamide (20 ml). Heat to 100° C. After 48hours, cool, pour into water (150 ml), and extract with ether. Combinethe organic layers and wash sequentially with distilled water and brineand then dry (Na₂SO₄), filter, and concentrate to give a residue.Chromatograph the residue eluting with 9:1 hexane:EtOAc to give thetitle compound.

EXAMPLE 14 6-Bromo-1H-indole

Combine 4-bromo-2-nitrotoluene (5.0 g, 23.1 mmol), dimethylformamide (50ml), DMF-dimethylacetal (9.0 ml, 69.4 mmol), and pyrrolidine (2.0 ml,23.1 mmol). Heat to 110° C. After 3 hours, cool to room temperature,dilute with ether, and wash with water. Combine the organic layers, andconcentrate to give a residue. Combine the residue and 80% aq. aceticacid (120 ml) and heat at 75° C. Add zinc dust (13.1 g, 200.5 mmol)portionwise. Heat to 85° C. After 2 hours, cool and filter. Dilute thefiltrate with ether, wash with water dry (Na₂SO₄), and concentrate togive a residue. Chromatograph the residue eluting with 9:1 hexane:EtOActo give the title compound.

By the method of Example 14 the following compounds were prepared:4-Bromo-1H-indole.

EXAMPLE 15 1H-Indole-6-carbaldehyde

Combine hexane washed potassium hydride (1.3 g, 10.7 mmol) and ether (20ml). Cool to about 0° C. and add a solution of 6-bromo-1H-indole (2.1 g,10.7 mmol) in ether (5 ml). After 15 min, cool to about −78° C. and adda solution of t-butyllithium, 1.4 M solution in hexane (14.0 ml, 10.7mmol). After 10 min, add dimethylformamide (1.7 ml, 20.0 mmol) in ether(5 ml). Slowly warm to room temperature and then pour into a ice coldsolution of 1M phosphoric acid and extract with EtOAc. Combine theorganic layers and wash sequentially with distilled water and brine andthen dry (Na₂SO₄), filter, and concentrated to give a residue.Chromatograph the residue eluting with 9:1 hexane:EtOAc to give thetitle compound.

By the method of Example 15 the following compounds were prepared:1H-Indole-4-carbaldehyde.

EXAMPLE 16 1-Phenyl-1H-indole-6-carbaldehyde

Combine in a sealed tube 1H-indole-6-carbaldehyde 0.9 g, 6.2 mmol),copper(I) trifluoromethanesulfate-complex (0.2 g, 0.3 mmol),phenanthroline (1.3 g, 6.2 mmol), transdibenzylidenacetone (0.1 g, 0.3mmol), cesium carbonate (2.6 g, 7.9 mmol) and iodobenzene (1.6 ml, 14.3mmol) in xylene (40 ml). Heat at about 110° C. After 24 hours, cool toroom temperature, dilute with dichloromethane and saturated ammoniumchloride. Separate the layer and Extract the aqueous layer withdichloromethane. Combine the organic layers and wash sequentially withdistilled water and brine and then dry (Na₂SO₄), filter, andconcentrated to give a residue. Chromatograph the residue eluting with8:2 hexane:EtOAc to give the title compound.

By the method of Example 16 the following compounds were prepared:1-Phenyl-1H-indole-4-carbaldehyde.

EXAMPLE 17 3-Phenylsulfanylbenzaldehyde

Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (0.3 g, 1.1 mmol) andacetonitrile (8.0 ml) add a solution of hydrochloric acid (1N, 2.0 ml).After 18 hours, concentrate in vacuum to remove most of theacetonitrile, dilute with water and extract with ether. Combine theorganic extracts and wash once with saturated sodium bicarbonate, thenwith brine. Dry (Na₂SO₄) the organics, filter, and concentrated to givethe title compound.

By the method of Example 17 the following compounds were prepared: a)3-Benzenesulfonylbenzaldehyde;

-   b) 3-p-Tolylsulfanylbenzaldehyde;-   c) 3-(p-Tosyl)benzaldehyde;-   d) 3-Benzylaminobenzaldehyde;-   e) 3-Phenylaminobenzaldehyde;-   f) 3-Benzoylbenzaldehyde;-   g) 3-(α-Fluorobenzyl)benzaldehyde;-   h) 3-(4-Fluorophenoxy)benzaldehyde;-   i) 3-(2-Fluorophenoxy)benzaldehyde;-   j) 3-(3-Fluorophenoxy)benzaldehyde;-   k) 3-(Naphth-2-yloxy)benzaldehyde;-   l) 3-(Naphth-1-yloxy)benzaldehyde;-   m) 3-(Pyridin-3-ylamino)benzaldehyde;-   n) 3-(Pyridin-4-ylamino)benzaldehyde;-   o) 3-(Pyridin-2-ylamino)benzaldehyde; and-   p) 3-(Pyridin-2-yloxy)benzaldehyde.

EXAMPLE 18 2-Naphth-2-ylethylamine

Combine naphth-2-ylacetonitrile (1.0 g, 6.0 mmol) and nickel (II)chloride hexahydrate (0.7 g, 3.0 mmol) and tetrahydrofuran (30 ml). Adddropwise borane-tetrahydrofuran complex, 1M solution in tetrahydrofuran(24.0 ml, 24.0 mmol). After 1 hour, evaporate to give a residue.Chromatograph on silica gel eluting with 8:2 EtOAc:MeOH+2% NH₄OH) togive the title compound.

By the method of Example 18 the following compounds were prepared:2-Naphth-1-ylethylamine.

EXAMPLE 19 5-Methanesulfonyltryptamine

Combine 2-(3-Chloropropyl)-(1,3)-dioxolane (6.69 g, 44.5 mmol), (4methanesulfonylphenyl) hydrazine hydrochloride (9.92 g, 44.5 mmol), andNa₂HPO₄ (1.58 g, 11.1 mmol) in 300 ml of methanol/water (1:1). Heat toreflux. After 4.5 hours, cool to ambient temperature, then evaporate toresidue. Dissolve the residue in 1 N NaOH and extract withdichloromethane. Combine the organic extracts, wash with brine, dry(Na₂SO₄), filter, then concentrate to residue. Chromatograph the residueon silica gel eluting with dichloromethane/2N NH₃(methanol) (84/16) togive the title compound as a light brown solid: mp 134-138° C., MS(ACPI): m/e 239.1 (M+1). Analysis for C₁₁H₁₄N₂O₂S: Calcd: C, 55.44; H,5.92; N, 11.76; found: C, 55.33; H, 5.97; N, 11.48.

EXAMPLE 20 N-t-Butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine

Combine di-tert-butyl dicarbonate (1.2 g, 5.34 mmol), 6-chlorotryptamine(866.4 mg, 4.45 mmol)d and NaHCO₃ (598.2 mg) in dioxane (50 ml). Stir atambient temperature. After 15 hours, evaporate to residue, partition theresidue between water and dichloromethane. Separate the layer andextract the aqueous layer with dichloromethane. Combine the organicextracts, wash with brine, dry (Na₂SO₄), filter and then evaporated togive the title compound as a light yellow oil.

EXAMPLE 21A N-Methyl-2-(6-chloro-1H-indol-3-yl)ethylamine

Combine N-t-butoxycarbonyl-2-(6-chloro-1H-indol-3-yl)ethylamine (1.3 g,4.41 mmol) and dry THF (20 ml) and add dropwise to an ice bath cooledsuspension of LiAlH₄ (1.0 g, 26.5 mmol) in dry THF (30 ml). Heat toreflux. After 2 hours, cool to ambient temperature and stir. After 15hours, quench with saturated NaSO₄ (100 ml/mol), stir for 1 hour atambient temperature, then filter under vacuum. Wash precipitate with THFand evaporated filtrate and washes to residue. Chromatograph the residueon silica gel eluting with dichloromethane/2N NH₃(methanol) (84/16) togive the title compound: MS (ACPI): m/e 209.0 (M+1).

EXAMPLE 21B 5-(4-Fluorophenyl)-1H-indole

Combine 5-bromoindole (5.00 g, 25.50 mmol) and Pd(Ph₃P)₄ (1.47 g, 1.28mmol) in toluene (510 ml). After 30 minutes, add a solution of4-fluorobenzeneboronic acid (5.35 g, 38.26 mmol) in ethanol (153 ml)then add saturated NaHCO₃ (255 ml). Heat to reflux. After 4 hours, coolto ambient temperature, pour into saturated NaCl (250 ml), and separatethe organic layer. Extract the aqueous layer with ethyl acetate. Combinethe organic extracts, wash with brine, dried, then evaporate to residue.Chromatograph the residue on silica gel eluting with ethylacetate/hexanes (10/90) to give the title compound: mp 84-89° C. MS(ACPI): m/e 212.0 (M+1). Analysis for C₁₄H₁₀FN: Calcd: C, 79.60; H,4.77; N, 6.63; found: C, 79.33; H, 4.92; N, 6.64.

By the method of Example 21 the following compounds were prepared: a)5-Phenyl-1H-indole: mp 71-74° C. MS (ACPI): m/e 194.0 (M+1). Analysisfor C₁₄H₁₁N: Calcd: C, 87.01; H, 5.74; N, 7.25; found: C, 86.67; H,5.82; N, 7.31.

b) 4-Phenylphenethylamine hydrochloride: (Exception-Chromatograph theresidue on silica gel using dichloromethane/2N N₃(methanol) (90/10) togive the final product. The HCl salt was prepared in ethyl acetate: MS(ACPI): m/e 198.1 (M+1). Analysis for C₁₄H₁₆ClN: Calcd: C, 71.94; H,6.90; N, 5.99; found: C, 71.66; H, 6.90; N, 5.94.

EXAMPLE 22 7-Cyano-1H-indole

Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g,48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to 200° C. After 2.5hours, cool to room temperature, add water-ethyl acetate (200 mL, 1/1)to give a solid. Filter through the celite, extract the filtrate withethyl acetate, combine the organic layers, wash with brine, dry overNa₂SO₄, filter and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with hexanes:ethyl acetate (10:1) togive (1.87 g) of the title compound as a yellow solid: ¹H NMR (300 MHz,DMSO-d₆)) 6.64-6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz), 7.51-7.53 (m, 1H),7.60-7.62 (m, 1H), 7.94 (d, 1H, J=8.0H), 12.03 (br, 1H).

EXAMPLE 23 3-Formyl-5-cyano-1H-indole

Add phosphorous oxychloride (11.76 g, 76.67 mmol) dropwise to DMF (24.3ml) wile maintaining the temperature at less than 110° C. Warm toambient temperature and stir for 15 minutes at ambient temperature. Adddropwise 5-cyanoindole (10.00 g, 70.34 mmol) as a solution in DMF (30ml) while keeping the temperature below 35°. After 1 hour, pour thereaction mixture into ice/water (300 ml) and then add 5N NaOH (54 ml)with stirring. Add slowly an additional amount of 5N NaOH (19.7 ml) andthen heated to 90° for 1 minute and then cooled to ambient temperatureto give a precipitate. Filter the precipitate and washed with water anddry to give the title compound: mp 248-250° C. MS (ACPI): m/e 171.0(M+1). Analysis for C₁₀H₆N₂O: Calcd: C, 70.58; H, 3.55; N, 16.46; found:C, 70.41; H, 3.53; N, 16.33.

By the method of Example 23 the following compounds were prepared: a)3-Formyl-5-(4-fluorophenyl)-1H-indole; mp 215-217° C. MS (ACPI): m/e239.1 (M+1). Analysis for C₁₅H₁₀FNO: Calcd: C, 75.30; H, 4.21; N, 5.85;found: C, 74.94; H, 4.17; N, 5.84;

b) 3-Formyl-5-phenyl-1H-indole; mp>250° C. MS (ACPI): m/e 222.1 (M+1).Analysis for C₁₅H₁₁NO: Calcd: C, 81.43; H, 5.01; N, 6.33; found: C,81.04; H, 5.05; N, 6.36;

c) 3-Formyl-6-methyl-1H-indole; mp 178-180° C. MS (ACPI): m/e 159.9(M+1). Analysis for C₁₀H₉NO: Calcd: C, 75.45; H, 5.70; N, 8.80; found:C, 75.60; H, 5.78; N, 8.97;

d) 3-Formyl-6cyano-1H-indole; mp 246° C. MS (ACPI): m/e 171.0 (M+1).Analysis for C₁₀H₆N₂O: Calcd: C, 70.58; H, 3.55; N, 16.46; found: C,70.51; H, 3.59; N, 16.40; and

e) 3-Formyl-6-trifluoromethoxy-1H-indole; mp 189-192° C. MS (ACPI): m/e230.0 (M+1). Analysis for C₁₀H₆F₃NO₂: Calcd: C, 52.41; H, 2.64; N, 6.11;found: C, 52.31; H, 2.61; N, 6.09.

f) 3-Formyl-7-cyano-1H-indole; ¹H NMR (300 MHz, DMSO-d₆) δ 7.41 (t, 1H,J=7.6 Hz), 7.80-7.82 (m, 1H), 8.42-8.50 (m, 2H), 10.02 (s 1H), 13.06(br, 1H).

g) 3-Formyl-6-bromo-1H-indole; mp 197-200° C. Analysis for C₉H₆BrNO:Calcd: C, 48.25; H, 2.70; N, 6.25; found: C, 47.87; H, 2.68; N, 6.17.

h) 3-Formyl-7-fluoro-1H-indole; mp 211-214° C. MS(ACPI): m/e 163.9(M+1). Analysis for C₉H₆FNO: Calcd: C, 66.26; H, 3.71; N, 8.59; found:C, 66.12; H, 3.67; N, 8.56.

EXAMPLE 25 3-(2-Nitrovinyl)-5-cyano-1H-indole

Combine 3-formyl-5-cyano-1H-indole (10.60 g, 63.32 mmol) and a solutionof ammonium acetate (10.60 g) in nitromethane (660 ml). Heat to 90° C.After 2 hours, cool to ambient temperature to give a precipitate.Collect the precipitate by filtration, wash with 1:1 MeOH/water (500ml), and dry to give the title compound: mp 247-251° C. MS (ACPI): m/e214.0 (M+1).

By the method of Example 25 the following compounds were prepared: a)3-(2-Nitrovinyl)-5-(4-fluorophenyl)-1H-indole; mp 217-220° C. MS (ACPI):m/e 282.2 (M+1). Analysis for C₁₅H₁₀FN₂O₂: Calcd: C, 68.08; H, 3.93; N,9.92; found: C, 67.73; H, 3.92; N, 9.73;

b) 3-(2-Nitrovinyl)-5-phenyl-1H-indole; MS (ACPI): m/e 265.1 (M+1);

c) 3-(2-Nitrovinyl)-6-methyl-1H-indole; MS (ACPI): m/e 203.1 (M+1);

d) 3-(2-Nitrovinyl)-6-cyano-1H-indole; mp>250° C. MS (ACPI): m/e 212.0(M−1). Analysis for C₁₁H₇N₃O₂: Calcd: C, 61.97; H, 3.31; N, 19.71;found: C, 62.09; H, 3.34; N, 20.06; and

e) 3-(2-Nitrovinyl)-6-trifluororo methoxy-1H-indole; mp 139-143° C. MS(ACPI): m/e 273.0 (M+1).

f) 3-(2-Nitrovinyl)-6-phenoxy-1H-indole: ¹H NMR (DMSO d6) 12.1 (s, 1H),8.38-8.34 (d, 1H), 8.20-8.19 (m, 1H), 8.01-7.97 (m, 2H), 7.39-7.35 (m,2H), 7.14-7.07 (m, 2H), 7.02-7.00 (m, 2H), 6.95-6.92 (m, 1H).

g) 3-(2-Nitro-vinyl)-5-(pyridin-3-yloxy)-1H-indole: ISMS 282 (M+1); ¹HNMR (DMSO-d₆) 9.5 (bs, 1H), 8.36-8.32 (m, 2H), 8.26-8.24 (m, 2H),7.98-7.95 (m, 1H), 7.79-7.78 (m, 1H), 7.55-7.53 (m, 1H), 7.34-7.31 (m,1H), 7.27-7.24 (m, 1H), 7.02-7.00 (m, 1H).

h) 3-(2-Nitro-vinyl)-7-cyano-1H-indole: ¹H NMR (300 MHz, CDCl₃) δ 7.36(t, 1H, J=7.7 Hz), 7.76 (d, 1H, J=7.2 Hz), 8.09-8.14 (m, 1H), 8.36-8.46(m, 3H); MS (electrospray), m/e: 212.1 (M−1)

i) 3-(2-Nitrovinyl)-6-bromo-1H-indole; mp 210° C., dec. Analysis forC₁₀H₇BrN₂O₂: Calcd: C, 44.97; H, 2.64; N, 10.49; found: C, 44.62; H,2.70; N, 10.49.

j) 3-(2-Nitrovinyl)-7-fluoro-1H-indole; mp 176-180° C. MS (ACPI): m/e207.1 (M+1). Analysis for C₁₀H₇FN₂O₂: Calcd: C, 58.26; H, 3.42; N,13.59; found: C, 58.01; H, 3.31; N, 13.26.

EXAMPLE 26 3-(2-Nitroethyl)-5-cyano-1H-indole

Add sodium borohydride (25.65 g, 678 mmol) to an ice bath cooledsolution of 3-(2-nitrovinyl)-5-cyano-1H-indole (12.68 g, 59.5 mmol) in1:1 MeOH/DMF (600 ml). After 1.5 hours, add brine (600 ml) then adjustthe pH to approximately 7 with 5N HCl. Evaporate under reduced pressureto remove the methanol and then extract with dichloromethane. Combinethe organic extracts, wash with brine, dry (Na₂SO₄), then evaporate toresidue. Chromatograph the residue on silica gel eluting withdichloromethane to give, after evaporation, the title compound ascolorless prisms: mp 132-136° C. MS (ACPI): m/e 215.0 (M+1). Analysisfor C₁₁H₉N₃O₂: Calcd: C, 61.39; H, 4.22; N, 19.52; found: C, 61.09; H,4.10; N, 19.16.

By the method of Example 26 the following compounds were prepared: a)3-(2-nitro-ethyl)-7-cyano-1H-indole; ¹H NMR (300 MHz, DMSO-d₆) 3.39 (t,2H, J=6.9 Hz), 4.87 (t, 2H, J=7.0 Hz), 7.17 (t, 1H, J=7.4 Hz), 7.38 (m,1H), 7.63 (d, 1H, J=7.4 Hz), 7.99 (d, 1H, J=7.9 Hz), 11.96 (br, 1H). MS(electrospray), m/e: 214.1 (M−1).

EXAMPLE 27 5-Cyanotryptamine

Add zinc powder (16.22 g, 248.1 mmol) in four portions to 2N HCl (300.0ml). Add dropwise 3-(2-nitroethyl)-5-cyano-1H-indole (2.25 g, 10.5 mmol)as a solution in methanol (300.0 ml). Heat to reflux. After 2.5 hours,cool to ambient temperature and adjust the pH to 11 using 5N NaOH,filter through Celite, wash with water, then extract the filtrate withdichloromethane. Combine the organic extracts, wash with brine, dry(Na₂SO₄), then evaporated to give the title compound: mp 102-105° C., MS(ACPI): m/e 186.1 (M+1). Analysis for C, H₁₁N₃: Calcd: C, 71.33; H,5.99; N, 22.69; found: C, 71.03; H, 5.91; N, 22.64.

By the method of Example 27 the following compounds were prepared: a)3-(2-aminoethyl)-7-cyano-1H-indole; ¹H NMR (300 MHz, DMSO-d₆) 2.76-2.82(m, 4H), 7.15 (t, 1H, J=7.6 Hz), 7.31 (s, 1H), 7.58 (d, 1H, J=7.4 Hz),7.91-7.94 (m, 1H), 11.80 (br, 1H); MS (electrospray), m/e: 186.1 (M+1),184.1 (m−1).

By the method of Example 27 the following compound was prepared: a)6-Bromotryptamine; mp 114-116° C. Analysis for C₁₀H₁₁BrN₂: Calcd: C,50.23; H, 4.64; N, 11.72; found: C, 49.96; H, 4.49; N, 11.47.

EXAMPLE 28 N-t-Butoxycarbonyl-2-(5-cyano-1H-indol-3-yl)ethylamine

Combine di-tert-butyl dicarbonate and a solution of 5-cyanotryptamine(1.33 g, 7.15 mmol) and 2N NaOH (4.2 ml) in THF (60 ml). After 3 hoursat ambient temperature, evaporate to residue. Dissolve the residue inwater and extract with dichloromethane. Combine the organic extracts,wash with brine, dry (Na₂SO₄), and evaporate to residue. Chromatographthe residue on silica gel eluting with dichloromethane/2N NH₃(methanol)(97/3)) to give the title compound: mp 129-132° C. MS (ACPI): m/e 286.2(M+1). Analysis for C₁₆H₁₉N₃O₂: Calcd: C, 67.35; H, 6.71; N, 14.73;found: C, 67.16; H, 6.68; N, 14.46.

By the method of Example 28 the following compounds were prepared: a)N-t-Butoxycarbonyl-2-(6-cyano-1H-indol-3-yl)ethylamine.

EXAMPLE 29 N-t-Butoxycarbonyl-2-(5-amido-1H-indol-3-yl)ethylamine

Combine water (64.0 ml) and NaOH (8.53 g) and cool to about 5° C. in anice bath. Add a solution ofN-t-butoxycarbonyl-2-(5-cyano-1H-indol-3-yl)ethylamine (1.85 g, 6.50mmol) in ethanol (128.0 ml) then added to the chilled solution. Adddropwise 30% peroxide (6.4 ml) while keeping the temperature below 5° C.After 30 minutes, warm to ambient temperature. After 22 hours, decomposethe excess peroxide by adding a 20% sodium bisulfite solution (45.0 ml)with stirring. After 30 minutes, evaporate under reduced pressure toremove the ethanol and extract the resulting aqueous solution with ethylacetate. Combine the organic extracts, wash with brine, dry (Na₂SO₄),then evaporate to residue. Chromatograph the residue on silica geleluting with dichloromethane/2N NH₃(methanol) (96/4) to give, afterevaporation, the title compound: mp 65-68° C. MS (ACPI): m/e 304.2(M+1). Analysis for C₁₆H₂₁N₃O₃: Calcd: C, 63.35; H, 6.98; N, 13.85;found: C, 63.26; H, 6.99; N, 13.71.

By the method of Example 28 the following compounds were prepared: a)N-t-Butoxycarbonyl-2-(6-amido-1H-indol-3-yl)ethylamine: MS (ACPI): m/e302.3 (M−1).

EXAMPLE 30 5-Amidotryptamine

Dissolve N-t-butoxycarbonyl-2-(5-amido-1H-indol-3-yl)ethylamine (1.83 g,6.04 mmol) in dioxane (25.0 ml). Add dropwise a 4M HCl in dioxane (7.5ml). After 18 hours, collect the solid by filtration and wash withdiethyl ether to give, after drying, the title compound as thehydrochloride: mp 192-195° C. MS (ACPI): m/e 202.0 (M+1).

By the method of Example 30 the following compounds were prepared: a)6-Amidotryptamine: mp 169-173° C. MS (ACPI): m/e 204.1 (M+1).

EXAMPLE 32 5-(4-Fluorophenyl)tryptamine

Combine LiAlH₄ (2.66 g, 70.17 mmol) and dry THF (70.0 ml) and cool thesuspension in an ice bath. Add dropwise a solution of5-(4-fluorophenyl)-3-(2-nitrovinyl)-1H-indole (3.30 g, 11.69 mmol) indry THF (30.0 ml). Heat to reflux. After 1 hour, cool to ambienttemperature and stir. After 15 hours, quench with saturated Na₂SO₄ (100ml/mol) and stir at ambient temperature. After 1 hour, filter, rinse theprecipitate with THF, and evaporate the filtrate to residue.Chromatograph the residue on silica gel eluting with dichloromethane/2NNH₃(methanol) (80/20) to give the title compound. Prepare the HCl saltin diethyl ether: mp>250° C. MS (ACPI): m/e 255.0 (M+1). Analysis forC₁₆H₁₆ClFN₂: Calcd: C, 66.09; H, 5.55; N, 9.63; found: C, 65.78; H,5.48; N, 9.58.

By the method of Example 32 the following compounds were prepared: a)5-Phenyltryptamine; mp 244-246° C. MS (ACPI): m/e 237.1 (M+1). Analysisfor C₁₆H₁₇ClN₂: Calcd: C, 70.45; H, 6.28; N, 10.27; Found: C, 70.75; H,6.33; N, 10.27. (isolated as the hydrochloride);

b) 6-Methyltryptamine; mp 139-141° C. MS (ACPI): m/e 175.0 (M+1).Analysis for C₁₁H₁₄N₂: Calcd: C, 75.82; H, 8.10; N, 16.08; Found: C,76.05; H, 8.26; N, 16.12.

c) 6-Trifluoromethoxtryptamine; MS (ACPI): m/e 245.0 (M+1). Analysis forC₁₁H₁₁F₃N₂O: Calcd: C, 54.10; H, 4.54; N, 11.47; Found: C, 53.92; H,4.50; N, 11.06.

d) 7-Fluorotryptamine; MS (ACPI): m/e 179.0 (M+1). Analysis forC₁₀H₁₁FN₂: Calcd: C, 67.40; H, 6.22; N, 15.72; Found: C, 67.06; H, 6.11;N, 15.48.

EXAMPLE 33 6-Ethoxycarbonyl-1H-indole

Combine 6-carboxy-1H-indole and ethanol (110 ml) and cool to 5° C. Adddropwise concentrated H₂SO₄ (96%, 11.08 ml) while keeping thetemperature below 10° C. Heat to reflux. After 4 hours, cool and pouronto ice/water, adjust the pH to about pH 9 and extract with ethylacetate. Combine the organic extracts, wash with brine, dry (Na₂SO₄),then concentrate to residue. Chromatograph the residue on silica geleluting with chloroform to give, after evaporation, the title compound:mp 72-75° C. MS (ACPI): m/e 189.9 (M+1).

EXAMPLE 34 3-(2-Nitrovinvyl-6-ethoxycarbonyl-1H-indole

Combine 1-dimethylamino-2-nitroethylene (1.93 g, 16.58 mmol) and TFA(10.0 ml) and stir until dissolved. Add 6-ethoxycarbonyl-1H-indole (3.14g, 16.58 mmol) and stir at ambient temperature. After 1 hour, pour thereaction mixture into ice/water, extract with ethyl acetate, thenevaporate to residue. Stir the residue in warm ethanol, cool to ambienttemperature, then filter and dry to give the title compound as a darkyellow powder: mp 241° C. MS (ACPI): m/e 261.1 (M+1). Analysis forC₁₃H₁₂N₂O₄: Calcd: C, 60.00; H, 4.65; N, 10.76; found: C, 59.99; H,4.63; N, 10.59.

EXAMPLE 35 3-(2-Nitroethyl)-6-ethoxycarbonyl-1H-indole

Combine 3-(2-nitrovinyl)-6-ethoxycarbonyl-1H-indole (4.0 g, 15.37 mmol)and NaBH₄ (726.7 mg, 19.21 mmol) in 100 ml of THE/Methanol (9:1) andstir at ambient temperature. After 1.5 hours, concentrate to residue.Partition the residue between brine and ethyl acetate, wash with brine,combine the organic layers, dry (Na₂SO₄), then evaporate to give thetitle compound as a yellow powder: mp 124-127° C. MS (ACPI): m/e 263.0(M+1). Analysis for C₁₃H₁₄N₂O₄: Calcd: C, 59.54; H, 5.38; N, 10.68;found: C, 59.40; H, 5.36; N, 10.53.

By the method of Example 35 the following compounds were prepared: a)3-(2-Nitroethyl)-6-cyano-1H-indole: m/e 214.1 (M−1). Analysis forC₁₁H₉N₃O₂: Calcd: C, 61.39; H, 4.22; N, 19.52; found: C, 61.05; H, 4.09;N, 19.19.

b) 3-(2-Nitroethyl)-6-bromo-1H-indole;

c) 3-(2-Nitroethyl)-6-methanesulfonyl-1H-indole; mp 162-164° C. MS(ACPI): m/e 269.1 (M+1).

d) 3-(2-Nitroethyl)-6-benzenesulfonyl-1H-indole (exception: 75 ml of THFwas used).

EXAMPLE 36 6-Ethoxycarbonyltryptamine

Combine Pt₂O (440 mg) and a solution of3-(2-nitroethyl)-6-ethoxycarbonyl-1H-indole (3.55 g, 13.54 mmol) inethyl acetate (100 ml). Hydrogenate at 60 psi (410 kPa) and ambienttemperature. After 4 hours, filter through celite and concentrate thefiltrate to residue. Chromatograph the residue on silica gel elutingwith dichloromethane/2N NH₃(methanol) (85/15) to give, afterevaporation, the title compound as an off-white powder: mp 127-131° C.MS (ACPI): m/e 233.0 (M+1). Analysis for C₁₃H₁₆N₂O₂: Calcd: C, 67.22; H,6.94; N, 12.06; found: C, 66.87; H, 6.86; N, 11.86.

By the method of Example 36 the following compounds were prepared: a)6-Cyanotryptamine: mp 144-147° C. MS (ACPI): m/e 186.0 (M+1). Analysisfor C₁₁H₁₁N₃: Calcd: C, 71.33; H, 5.99; N, 22.69; found: C, 71.10; H,5.89; N, 22.38.

b) 6-Methanesulfonyltryptamine: mp 149-153° C. MS (ACPI): m/e 239.1(M+1). Analysis for C, 1H₁₄N₂O₂S: Calcd: C, 55.44; H, 5.92; N, 11.76;found: C, 55.12; H, 5.82; N, 11.97.

c) 6-Benzenesulfonyltryptamine: mp 169-172° C. MS (ACPI): m/e 301.0(M+1).

EXAMPLE 38 6-Trifluoromethoxy-1H-indole

Combine 1-methyl-4-trifluoromethoxybenzene (5.44 g, 30.87 mmol) andH₂SO₄ (96%, 30.9 ml). Cool to about 0° C. Add dropwise filming HNO₃(2.06 g, 32.72 mmol) while maintaining the temperature below 10° C. Whenthe addition is complete, warm to ambient temperature. After 2.5 hours,pour the mixture onto ice/water, extract with dichloromethane. Combinethe organic extracts, wash with brine, dry (Na₂SO₄), then concentrate toresidue. Chromatograph the residue on silica gel eluting withhexanes/ethyl acetate (75/25) to give, after evaporation,1-methyl-2-nitro-4-trifluoromethoxybenzene: MS (ACPI): m/c 220.1 (M−1).

Combine 1-methyl-2-nitro-4-trifluoromethoxybenzene (3.73 g, 16.86 mmol),pyrrolidine (1.32 g, 18.55 mmol), N,N-dimethylformamide dimethyl acetal(6.03 g, 50.58 mmol), and dry DMF (35 ml). Heat to about 1050. After 19hours, remove the DMF under reduced pressure to give an oily residue.Combine the residue and ethyl acetate, wash with brine, dry (Na₂SO₄),then concentrate to giveN,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine.

Combine N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine(4.64 g, 16.8 mmol) and Raney® nickel (900 mg) in ethanol (100 ml).Hydrogenate at 60 psi (410 kPa). and ambient temperature. After 18hours, filter through celite, concentrate the filtrate to residue, andchromatograph on silica gel eluting with hexanes/ethyl acetate (30/70)to give, after evaporation, the title compound as an off-white powder:mp 59° C. MS (ACPI): m/e 200.0 (M−1).

EXAMPLE 39 2-Phenylphenethylamine

Combine 2-phenylphenylacetonitrile (4.69 g, 24.26 mmol) and diethylether (10 ml) and add dropwise to a cooled (−10°) solution of LiAlH₄(2.76 g, 72.81 mmol) in diethyl ether (100 ml). Warm to ambienttemperature. After 2 hours, quench with saturated sodium sulfate (100ml/mol). Filter to remove the precipitate, dry (Na₂SO₄) the filtrate,filter, and concentrate to residue. Chromatograph the residue on silicagel eluting with dichloromethane/2N NH₃(methanol) (95/5) to give thetitle compound as a yellow oil. Prepare the HCl salt in diethyl ether:mp 197-199° C. MS (ACPI): m/e 198.1 (M+1). Analysis for C₁₄H₁₆ClN:Calcd: C, 71.94; H, 6.90; N, 5.99; found: C, 72.15; H, 6.84; N, 6.09.

EXAMPLE 40 7-Chloro-1H-indole

By the method of J. Med. Chem. 1990, 33, 2777), add dropwise2-chloroaniline (5.8 g, 45.45 mmol) in anhydrous toluene (80 mL) to acold 1M solution of BCl₃ (50 mL) in dichloromethane. After addition,allow the reaction to stir at 0° C. for 10 minutes. After 10 minutes at0° C., add chloroacetonitrile (13.72 g, 11.53 mL, 181.8 mmol, 4 eq) andaluminum trichloride (6.67 g, 50 mmol, 1.1 eq) in 5 equal portions over45 minutes and then beat to reflux (˜65° C.). After 6 hours, cool toroom temperature. After 16 hours, cool the reaction in an ice bath andadd 2N HCl (61.4 mL) and then heat the reaction to reflux. After 45minutes, cool in an ice bath, neutralize the acid with 2N NaOH keepingthe temperature of the reaction below 15C.° until the pH is about S.Transfer the reaction to a separatory funnel and remove the organiclayer. Extract the aqueous layer with dichloromethane (2×200 mL).Combine the organic layers, dry over MgSO₄, filter, and remove thesolvent in vacuo to give 1-(2-amino-3-chlorophenyl)-2-chloroethanonewhich may be used without further purification.

Dissolve 1-(2-amino-3-chlorophenyl)-2-chloroethanone (7.0 g, 34.30 mmol)in 10% aqueous 1,4-dioxane (75 mL). Carefully add NaBH₄ (2.6 g, 68.6mmol, 2 eq.) as a solid. Heat to reflux. After 4 hours, cool to roomtemperature, dilute with water (300 mL), and extract withdichloromethane (2×200 mL). Combine the organic layers, dry over MgSO₄,filter, and remove the solvent in vacuo leaving a light brown oil in theflask. Purify the oil by HPLC (silica gel mobile phase: 100% hexane to50% EtOAc in hexanes over 50 minutes), to give the title compound as abrown oil: ¹H NMR (300 MHz, d6-DMSO-d6): 5.16 (m, 1H), 5.39 (d, 1H),5.70 (bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES+): m/z 154, 152(M+H)⁺.

By the method of Example 40 the following compounds were prepared: a)5-Bromo-7-ethyl-1H-indole: ¹H NMR (300 MHz, d6-DMSO-d6): 1.25 (t, 3H),2.85 (m, 2H), 6.41 (m, 1H), 7.02 (M, 1H), 7.36 (m, 1H), 7.55 (m, 1H),11.28 (bs, 1H); MS(ES+): m/z 224, 226 (M+H)⁺; Analysis for C₁₀H₁₀BrN:Calcd.; C, 53.60; H, 4.50; N, 6.25; found; C, 53.50; H, 4.34; N, 6.22.

EXAMPLE 42 6-Trifluoromethyl-1H-indole

Combine 2-bromo-5-trifluoromethylphenylamine (27.06 g, 112.74 mmol) and200 mL of pyridine. Cool in an ice bath and add ethyl chloroformate(18.35 g, 169.11 mL, 1.5 eq). After addition was complete, allow thereaction to gradually warming to room temperature. After 18 hours,evaporate in vacuo to give a residue. Dissolve the residue in Et₂O/waterand transfer to a separatory funnel. Separate the layer and extract theaqueous layer with Et₂O (2×300 mL), combine the organic layers, dry overMgSO₄, filter, and evaporate in vacuo to giveN-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester which maybe used without further purification.

Following the procedure described in J. Org. Chem. 1997, 62, 6507,combine N-(2-bromo-5-trifluoromethylphenyl)carbamic acid ethyl ester(34.33 g, 110 mmol), triethylamine (300 mL),dichlorobis(triphenylphosphine)palladium(II) (5.4 g, 7.7 mmol), andcopper (I) iodide (1.47 g, 7.7 mmol). Evacuate the dark solution andfill with N₂ twice and then quickly add (trimethylsilyl)acetylene (16.21g, 165 mmol, 23.32 mL) with vigorous stirring. Heat to 80° C. When TLCindicates absence of the starting material, add water and Et₂O andfilter through celite and evaporate the filtrate in vacuo to give aresidue. Dilute residue with water and extract with Et₂O, combine theorganic layers and remove the evaporate to give a dark brown oil. Absorbthe oil onto silica gel and load onto a short column of silica gelequilibrated with 100% hexanes. Wash with 100% hexanes (2 L) and elutethe product with 1% EtOAc in hexanes. Pool fractions containing theproduct and remove in vacuo the solvent to give5-trifluoromethyl-2-trimethylsilanylethynyl phenylamine as a red/brownoil; MS (IS): m/z 330 (M+H)⁺.

Carefully add NaH (10.83 g, 60% in oil, 270.8 mmol, 4 eq.) to EtOH (200mL). When cool, add a solution of5-trifluoromethyl-2-trimethylsilanylethynylphenylamine (22.3 g, 67.7mmol) in EtOH (400 mL) with vigorous stirring. After 2 hours, heat toreflux. After 4 hours, evaporate in vacuo to remove the EtOH and dilutethe residue obtained with water and extract with Et₂O. Combine theorganic layers and wash with brine, dry over MgSO₄, filter, andevaporate to give a dark oil. Absorbed the oil onto silica gel and loadonto short column of silica gel. Elute with 20% EtOAc in hexanes. Poolfractions containing the product and remove the solvent leaving a darkbrown oil. Further purification of the oil by HPLC (silica column) usinga gradient 1% Et₂O in hexanes to 15% Et₂O in hexanes. Pool fractionscontaining the product and remove the solvent to give the title compoundas an orange solid: ¹H NMR (300 MHz, d6-DMSO-d6): 6.58 (m, 1H), 7.28 (m,1H), 7.61 (t, 1H), 7.74 (m, 2H), 11.51 (bs, 1H); MS(EI+): m/z 185 (M+).

By the method of Example 42 the following compounds were prepared: a)5-Isopropyl-1H-indole: MS(ES+): m/z 160 (M+H)⁺; (ES)−: m/z 158 (M−H)⁻.

EXAMPLE 44 6-Fluoro-5-methoxy-1H-indole

Dissolve fuming nitric acid (24 mL) in concentrated H₂SO₄ in a roundbottom flask. Add 3,4-difluorobromobenzene (20 g, 104 mmol) dropwise viapipette with vigorous stirring. After addition, stir the reaction atroom temperature for 2 hours, pour the reaction into ice water andextract with Et₂O (2×250 mL). Collect and combine the organic layers,dry over MgSO₄, filter, and remove the solvent to give1-bromo-4,5-difluoro-2-nitrobenzene as a light yellow oil.

Add 1-bromo-4,5-difluoro-2-nitrobenzene (24 g, 100 mmol) to a solutionof sodium methoxide (1.2 eq) in MeOH. After addition, stir the reactionat room temperature for 2.5 hours. Remove the solvent in vacuo anddilute the residue with water and extract with Et₂O (2×250 mL). Combinethe organic layers, dry over MgSO₄, filter, and the remove solvent invacuo to give 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene as a yellowsolid: ¹H NMR (300 MHz, CDCl₃): 3.99 (s, 3H), 7.26 (m, 1H), 7.83 (d,1H); MS(FD+): m/z 249, 251 (M+); Analysis for C₇H₅BrFNO₃: Calcd.: C,33.63; H, 2.02; N, 5.60; found: C, 33.79; H, 1.98; N, 5.62.

Combine 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.5 g, 82 mmol) andPt-on-carbon (sulfided) in THE (600 mL) and hydrogenate at 60 psi (414kPa) over for 4 hours. Filter the reaction through celite to remove thecatalyst and remove the solvent to give2-bromo-5-fluoro-4-methoxyaniline as a brown solid which may taken onwithout further purification.

Using 2-bromo-5-fluoro-4-methoxyaniline, the method of Example 42 givesN-(2-bromo-5-fluoro-4-methoxyphenyl)carbamic acid ethyl ester as a brownsolid: ¹H NMR (300 MHz, CDCl₃): 1.33 (t, 3H), 3.85 (s, 3H), 4.23 (q,2H), 7.09 (d, 1H), 7.97 (bd, 1H); MS(FD+): m/z 291, 293 (M+);N-(5-fluoro-4-methoxy-2-trimethylsilanylethynylphenyl)carbamic acidethyl ester as a yellow solid: MS(ES+): m/z 310 (M+H)⁺; (ES−): m/z 308(M−H)⁻; and the title compound as a solid: ¹H NMR (300 MHz, CDCl₃): 3.93(s, 3H), 6.48 (m, 1H), 7.15 (m, 3H), 8.11 (bs, 1H); MS(ES+): m/z 166(M+H)⁺; (ES−): m/z 164 (M−H)⁻; Analysis for C₉H₈FNO: Calcd.: C, 65.45;H, 4.88; N, 8.48; found: C, 65.17; H, 4.97; N, 8.70.

EXAMPLE 45 5,6-Difluoro-1H-indole

Using the method of Example 42 gives 2-bromo-4,5-difluoroaniline; whichgives N-(2-bromo-4,5-difluorophenyl)carbamic acid ethyl ester; whichgives N-(4,5-Difluoro-2-trimethylsilanylethynylphenyl)carbamic acidethyl ester; which gives the title compound as an orange solid: ¹H NMR(300 MHz, d6-DMSO-d6): 6.43 (m, 1H), 7.38 (m, 2H), 7.50 (m, 1H), 11.25(bs, 1H); MS(ES−): m/z 152 (M−H)⁻; Analysis for C₈H₅F₂N: Calcd.: C,62.75; H, 3.29; N, 9.15; found: C, 62.41; H, 3.12; N, 8.98.

EXAMPLE 46 5-Trifluoromethoxy-1H-indole

Using the method of Example 42 and 2-bromo-4-(trifluoromethoxy)anilinegives N-(2-bromo-4-trifluoromethoxyphenyl)carbamic acid ethyl ester: ¹HNMR (300 MHz, CDCl₃): 1.34 (t, 3H), 4.25 (m, 2H), 7.19 (m, 1H), 7.41 (m,1H), 8.20 (d, 1H); MS(ES−): m/z 326, 328 (M−H)⁻; Analysis forC₁₀H₉BrF₃NO₃: Calcd.; C, 36.6096; H, 2.7650; N, 4.2692; found; C, 36.50;H, 2.67; N, 3.97; which givesN-(4-Trifluoromethoxy-2-trimethylsilanylethynylphenyl)carbamic acidethyl ester; which gives the title compound as a yellow oil: MS(ES−):m/z 200 (M−H)⁻.

EXAMPLE 47 4-Phenyl-1H-indole

Using the method of Carrera and Sheppard in Synlett. 1994, 93-94,4-bromoindole gives the title compound: ¹H NMR (300 MHz, d6-DMSO-d6):6.56 (m, 1H), 7.08 (m, 1H), 7.17 (m, 1H), 7.43 (m, 5H), 7.67 (m, 2H),11.27 (bs, 1H); MS(ES+): m/z 194 (M+H)⁺; (ES−): m/z 192 (M−H)⁻.

EXAMPLE 48 (2-Nitro-5-trifluoromethylphenyl)-acetonitrile

By the method of Liebigs Ann. Chem. 1988, 203-208, using4-nitrobenzotrifluoride (15 g, 78.49 mmol) gives the title compound:MS(ES−): m/z 229 (M−H)⁻.

EXAMPLE 49 5-Trifluoromethyl-1H-indole

By the method of Liebigs Ann. Chem. 1988, 203-208 using(2-nitro-5-trifluoromethylphenyl)acetonitrile gives the title compoundas a white solid: ¹H NMR (300 MHz, d6-DMSO-d6): 6.60 (m, 1H), 7.36 (m,1H), 7.53 (m, 1H), 7.57 (m, 1H), 7.94 (m, 1H), 11.51 (bs, 1H); MS(ES−):m/z 184 (M−H)⁻.

EXAMPLE 50 3-Formyl-4-methoxy-1-indole

Add phosphorus oxychloride (1.1 eq.) with vigorous stirring to DMF(cooled in an ice bath). After the addition is complete, allow to stirin the ice bath for ˜10 minutes, then add a solution of4-methoxy-1H-indole (5 g) in anhydrous DMF with vigorous stirring. Allowto stir at 0° C. After 1 hour, warn to room temperature. After 16 hours,carefully add 4 eq. of 2N NaOH with vigorous stirring. Heat to about 80°C. and then cool. Pour the reaction mixture into cold water withvigorous stirring to give a solid. Collect the solid by filtration anddry in a vacuum oven at room temperature to give the title compound.Acidify the filtrate and extract with EtOAc. Combine the organic layersand wash with 50% brine. Collect the organic layer, dry (MgSO₄) filter,and remove the solvent to give the title compound as a light purplesolid. Total yield of the title compound is 5.44 g: MS (ES+): m/z 175(M+H)⁺, 160 (M−CH₃)⁺; (ES−): m/z 174 (M−H)⁻.

By the method of Example 50 the following compounds were prepared: a)3-Formyl-6-methoxy-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 3.79 (s, 3H);6.85 (dd, 1H); 6.98 (m, 1H); 7.92 (d, 1H); 8.15 (s, 1H); 9.86 (s, 1H);11.92 (bs, 1H); MS (ES+): m/z 176 (M+H)⁺; (ES−): m/z 174 (M−H)⁻;

b) 3-Formyl-7-methoxy-1H-indole;

c) 3-Formyl-4-chloro-1H-indole;

d) 3-Formyl-6-chloro-1H-indole, ¹H NMR (300 MHz, d6-DMSO-d6): 7.24 (dd,1H), 7.56 (d, 1H), 8.06 (d, 1H), 8.33 (s, 1H), 9.93 (s, 1H), 12.21 (bs,1H); MS (ES+): m/z 182, 180 (M+H)⁺; (ES−): m/z 180, 178 (M−H)⁻;

e) 3-Formyl-7-chloro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.23 (t, 1H),7.35 (d, 1H), 8.05 (d, 1H), 8.38 (bs, 1H), 9.95 (s, 1H), 12.54 (bs, 1H);MS (ES+): m/z 182, 180 (M+H)⁺; (ES−): m/z 180, 178 (M−H)⁻;

f) 3-Formyl-4-fluoro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.01 (m, 1H),7.24 (m, 1H), 7.36 (d, 1H), 8.30 (s, 1H), 10.03 (d, 1H), 12.48 (bs, 1H);MS (ES+): m/z 164 (M+H)⁺; (ES−): m/z 162 (M−H)⁻;

g) 3-Formyl-5-methoxy-6-trifluoromethyl-1H-indole, ¹H NMR (300 MHz,d6-DMSO): 3.91 (s, 3H), 7.77 (dd, 1H), 7.95 (bs, 1H), 8.42 (s, 1H), 9.96(s, 1H), 12.29 (bs, 1H); MS (ES+): m/z 244 (M+H)⁺; (ES−): m/z 242(M−H)⁻;

h) 3-Formyl-6-chloro-5-methoxy-1H-indole, ¹H NMR (300 MHz, d6-DMSO):3.88 (s, 3H), 7.58 (s, 1H), 7.71 (s, 1H), 8.26 (s, 1H), 9.91 (s, 1H),12.08 (bs, 1H); MS (ES+): m/z 210, 212 (M+H)⁺; (ES−): m/z 208, 210(M−H)⁻;

i) 3-Formyl-4-chloro-5-methoxy-1H-indole, ¹H NMR (300 MHz, d6-DMSO):3.89 (s, 3H), 7.13m (dd, 1H), 7.47 (dd, 1H), 8.23 (s, 1H), 10.5 (s, 1H),12.39 (bs, 1H); MS (ES+): m/z 210, 212 (M+H)⁺ (ES−): m/z 208, 210(M−H)⁻;

j) 3-Formyl-6-trifluoromethyl-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.52(d, 1H), 8.27 (d, 1H), 8.51 (m, 1H), 9.99 (s, 1H), 12.47 (bs, 1H).MS(ES+): m/z 214 (M+H)⁺; (ES−): m/z 212 (M−H)⁻;

k) 3-Formyl-5-methoxy-2-methyl-1H-indole, ¹H (300 MHz, d6-DMSO): 2.65(s, 3H), 3.76 (s, 3H), 6.78 (dd, 1H), 7.27 (d, 1H), 7.56 (m, 1H), 10.00(s, 1H), 11.85 (bs, 1H); MS(ES+): m/z 190 (M+H)⁺; (ES−): m/z 188 (M−H)⁻;

l) 3-Formyl-6-fluoro-5-methoxy-1H-indole, ¹H NMR (300 MHz, d6-DMSO):3.87 (s, 3H), 7.35 (d, 1H), 7.71 (d, 1H), 8.21 (s, 1H), 9.89 (s, 1H),12.03 (bs, 1 h); MS(ES+): m/z 194 (M+H)⁺; (ES−): m/z 192 (M−H)⁻;

m) 3-Formyl-5,6-difluoro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.56 (m,1H), 7.92 (m, 1H), 8.36 (s, 1H), 9.92 (s, 1H), 12.25 (bs, 1H); MS(ES+):m/z 182 (M+H)⁺; (ES−): m/z 180 (M−H)⁻;

n) 3-Formyl-6-chloro-5-fluoro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.72(d, 1H), 7.91 (d, 1H), 8.40 (s, 1H), 9.93 (s, 1H), 12.29 (bs, 1H);MS(ES+): m/z 198 (M+H)⁺; (ES−): m/z 196 (M−H)⁻;

o) 3-Formyl-5-trifluoromethoxy-1H-indole, ¹H NMR (300 MHz, d6-DMSO):7.24 (m, 1H), 7.61 (m, 1H), 7.97 (bs, 1H), 8.42 (d, 1H), 9.95 (s, 1H),12.35 (bs, 1H); MS(ES+): m/z 230 (M+H)⁺; (ES−): m/z 228 (M−H)⁻; Analysisfor C₁₀H₆F₃NO₂: Calcd.; C, 52.4138; H, 2.6391; N, 6.1122; found; C,52.70; H, 2.73; N, 6.13;

p) 3-Formyl-4,6-difluoro-5-methoxy-1H-indole, MS(ES+): 212 (M+H)⁺;(ES−): 210 (M−H)⁻;

q) 3-Formyl-4-phenyl-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.07 (m, 1H),7.30 (m, 1H), 7.46 (m, 6H), 7.53 (m, 1H), 8.20 (bs, 1H), 9.37 (s, 1H),12.40 (bs, 1H). MS(ES+): m/z 222 (M+H)⁺; (ES−): m/z 220 (M−H)⁻;

r) 3-formyl-6-phenyl-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.35 (m, 1H),7.49 (m, 3H), 7.71 (m, 3H), 8.15 (m, 1H), 8.33 (d, 1H), 9.96 (s, 1H),12.20 (bs, 1H). MS(EI+): m/z 221 (M)⁺;

s) 3-Formyl-5-isopropyl-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 1.24 (d,6H), 2.99 (m, 1H), 7.15 (m, 1H), 7.41 (m, 1H), 7.94 (m, 1H), 8.22 (m,1H), 9.90 (s, 1H), 12.02 (bs, 1H); MS(ES+): 188 (M+H)⁺; (ES−): m/z 186(M−H)⁻;

t) 3-Formyl-4,6-difluoro-5-methoxy-1-methyl-1H-indole: ¹H NMR (300 MHz,CDCl₃): 3.81 (s, 3H), 4.02 (s, 3H), 6.92 (m, 1H), 7.77 (s, 1H), 10.14(d, 1H); MS(ES+): m/z 226 (M+H)⁺; and

u) 3-Formyl-4,6-difluoro-1-methyl-1H-indole: ¹H NMR (300 MHz, d6-DMSO):3.87 (s, 3H), 7.10 (m, 1H), 7.41 (m, 1H), 8.32 (s, 1H), 9.93 (d, 1H);MS(ES+): 196 (M+H)⁺.

EXAMPLE 51 3-(2-Nitrovinyl)-4-methoxy-1H-indole

Combine ammonium acetate (dried from treatment with toluene and removalof the toluene in vacuo) as a solid (0.75 eq.), nitromethane (20 eq.),and 4-methoxy-1H-indole-3-carbaldehyde (5.4 g; 30.82 mmol). Heat toabout 65° C. After the reaction is judged to be near completion (byTLC), add silica gel and evaporate in vacuo to remove the nitromethane.Load the silica gel from the reaction mixture on top of short column ofsilica gel and elute with 25% acetone in hexanes to give, afterevaporation, the title compound which may be used in the next stepwithout further purification.

By the method of Example 51 the following compounds were prepared: a)3-(2-Nitrovinyl)-6-methoxy-1H-indole;

b) 3-(2-Nitrovinyl)-7-methoxy-1H-indole, ¹H NMR (300 MHz; d6-DMSO): 3.95(s, 3H), 5.02 (m, 1H), 6.86 (d, 1H), 7.17 (t, 1H), 7.50 (d, 1H), 8.38(d, 1H), 12.40 (bs, 1H); MS (ES+): m/z 219 (M+H)⁺; (ES−): m/z 217(M−H)⁻;

c) 3-(2-Nitrovinyl)-4-chloro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 5.08(m, 1H), 7.24 (m, 2H), 7.51 (dd, 1H), 8.12 (d, 1H), 8.92 (d, 1H), 12.6(bs, 1H); MS(ES−): m/z 221, 223 (M−H)⁻;

d) 3-(2-Nitrovinyl)-6-chloro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 5.03(m, 1H), 7.22 (dd, 1H), 7.58 (d, 1H), 8.03 (m, 2H), 8.38 (d, 1H), 12.23(bs, 1H); MS (ES−): m/z 223, 221 (M−H)⁻;

e) 3-(2-Nitrovinyl)-7-chloro-1H-indole, ¹H NMR (300 MHz, d6-DMSO): 7.23(t, 1H), 7.36 (d, 1H), 7.97 (d, 1H), 8.06 (d, 1H), 8.33 (bs, 1H), 8.40(d, 1H), 12.58 (bs, 1H); MS (ES+): m/z 225, 223 (M+H)⁺; (ES−): m/z 223,221 (M−H)⁻;

f) 3-(2-Nitrovinyl)-4-fluoro-1H-indole,

g) 3-(2-Nitrovinyl)-5-methoxy-6-trifluoromethyl-1H-indole, MS (ES+): m/z286 (M+); (ES−): m/z 285 (M−H)⁻;

h) 3-(2-Nitrovinyl)-6-chloro-5-methoxy-1H-indole,

i) 3-(2-Nitrovinyl)-4-chloro-5-methoxy-1H-indole, ¹H NMR (300 MHz,d6-DMSO): 3.88 (s, 3H), 5.03 (m, 2H), 7.13 (d, 1H), 7.46 (d, 1H), 8.08(d, 1H), 12.42 (bs, 1H); MS(ES−): m/z 151, 153 (M−H)⁻;

j) 3-(2-Nitrovinyl)-6-trifluoromethyl-1H-indole, MS(ES+): m/z 257(M+H)⁺; (ES−): m/z 255 (M−H)⁻;

k) 3-(2-Nitrovinyl)-5-methoxy-2-methyl-1H-indole, ¹H NMR (300 MHz,d6-DMSO): 2.58 (s, 3H), 3.84 (s, 3H), 6.82 (m, 1H), 7.28 (m, 2H), 7.89(d, 1H), 8.29 (d, 1H), 12.14 (bs, 1H); MS(ES+): m/z 233 (M+H)⁺; (ES−):m/z 231 (M−H)⁻;

l) 3-(2-Nitrovinyl)-6-fluoro-5-methoxy-1H-indole;

m) 3-(2-Nitrovinyl)-5,6-difluoro-1H-indole;

n) 3-(2-Nitrovinyl)-6-chloro-5-fluoro-1H-indole;

o) 3-(2-Nitrovinyl)-5-trifluoromethoxy-1H-indole;

p) 3-(2-Nitrovinyl)-4,6-difluoro-5-methoxy-1H-indole;

q) 3-(2-Nitrovinyl)-4-phenyl-1H-indole;

r) 3-(2-Nitrovinyl)-6-phenyl-1H-indole;

s) 3-(2-Nitrovinyl)-5-isopropyl-1H-indole;

t) 3-(2-Nitrovinyl)-4,6-difluoro-5-methoxy-1-methyl-1H-indole: ¹H NMR(300 MHz, d6-DMSO): 3.82 (t, 3H), 3.92 (s, 3H), 7.53 (m, 1H), 7.84 (m,1H), 8.30 (m, 2H); MS(ES+): m/z 269 (M+H)⁺; and

u) 3-(2-Nitrovinyl)-4,6-difluoro-1-methyl-1H-indole.

EXAMPLE 52 4-Methoxytryptamine

Combine LiAlH₄ (6.78 g; 178.74 mmol; 6 eq) and anhydrous THF. Dissolve3-(2-nitrovinyl)-4-methoxy-1H-indole (6.5 g; 29.79 mmol) in anhydrousTHF and add dropwise to the LiAlH₄ solution with vigorous stirring.After the addition is complete, heat to reflux. After 1 hour cool toambient temperature and stir. After 16 hours, quench the excess LiAlH₄as described in J. Med. Chem. 1995, 38, 2050. Filter the gray suspensionthrough celite and rinse the celite with ethyl acetate. Evaporate thefiltrate in vacuo to residue. Chromatograph the residue on silica geleluting with 1 L of CHCl₃/MeOH/NH₄OH (95:10:1) and then 1 L ofCHCl₃/MeOH/NH₄OH (90:10:1) as the mobile phase. Pool fractionscontaining the product and evaporate to give the title compound as a tansolid: ¹H NMR (300 MHz, d₆-DMSO): 2.96 (t, 2H); 3.42 (t, 2H); 3.83 (s,3H); 6.42 (dd, 1H); 6.93 (m, 3H); 10.7 (s, 1H); MS (ES+): m/z 191(M+H)⁺; 174 (M−NH₂)⁺; 159 (M−OCH₃)⁺; (ES−): m/z 189 (M−H)⁻.

By the method of Example 52 the following compounds were prepared: a)6-Methoxytryptamine, ¹H NMR (300 MHz; d6-DMSO): 2.86 (t, 2H); 3.42 (t,2H); 3.75 (s, 3H); 6.62 (dd, 1H); 6.83 (m, 1H); 6.97 (bs, 1H); 7.37 (m,1H); 10.55 (s, 1H); MS (ES+): m/z 191 (M+H)⁺; 174 (M−NH₂)⁺; (ES−): m/z189 (M−H)⁻;

b) 7-Methoxytryptamine, ¹H NMR (300 MHz, d6-DMSO): 2.88 (t, 2H), 3.42(t, 2H), 3.89 (s, 3H), 6.61 (d, 1H), 6.89 (t, 1H), 7.02 (m, 1H), 7.10(d, 1H), 10.85 (bs, 1H); MS (ES+): m/z 191 (M+H)⁺, 174 (M−NH₂); (ES−):m/z 189 (M−H)⁻;

c) 4-Chlorotryptamine, ¹H NMR (300 MHz, d6-DMSO): 3.11 (t, 2H), 3.44 (t,2H), 6.99 (m, 2H), 7.22 (m, 1H), 7.30 (d, 1H), 11.19 (bs, 1H); MS(ES+):m/z 178, 180 (M+H)⁺; (ES−): m/z 193 (M−H)⁻;

d) 6-Chlorotryptamine, ¹H NMR (300 MHz, d6-DMSO): 2.89 (t, 2H), 3.42 (t,2H), 6.96 (dd, 1H), 7.17 (bs, 1H), 7.35 (m, 1H), 7.52 (d, 1H), 10.91(bs, 1H); MS (ES+): m/z 197, 195 (M+H)⁺, 180, 178 (M−NH₂)⁺; (ES−): m/z195, 193 (M−H)⁻;

e) 7-Chlorotryptamine, ¹H NMR (300 MHz, d6-DMSO): 2.91 (t, 2H), 3.43 (t,2H), 6.98 (t, 1H), 7.13 (d, 1H), 7.20 (bs, 1H), 7.51 (d, 1H), 11.15 (bs,1H); MS (ES+): m/z 197, 195 (M+H)⁺, 180, 178 (M−NH₂)⁺; (ES−): m/z 195,193 (M−H)⁻;

f) 4-Fluorotryptamine,

g) 5-Methoxy-6-trifluoromethyltryptamine,

h) 6-Chloro-5-methoxytryptamine, ¹H NMR (300 MHz, d6-DMSO): 2.89 (t,2H), 3.42 (t, 2H), 3.84 (s, 3H), 7.12 (bs, 1H), 7.19 (s, 1H), 7.36 (s,1H), 8.01 (bs, 1H); MS (ES+): m/z 225, 227 (M+H)⁺, 208, 210 (M−NH₂)⁺;(ES−): m/z 223, 225 (M−H)⁻;

i) 4-Chloro-5-methoxytryptamine, ¹H NMR (300 MHz, d6-DMSO): 3.10 (t,2H), 3.43 (t, 2H), 3.81 (s, 3H), 6.95 (d, 1H), 7.18 (m, 1H), 7.25 (dd,1H), 10.93 (bs, 1H); MS(ES+): m/z 208, 210 (M−NH2)⁺ (ES−): m/z 223, 225(M−H)⁻;

j) 6-Trifluoromethyltryptamine,

k) 5-Methoxy-2-methyltryptamine, ¹H NMR (300 MHz, d6-DMSO): 2.28 (s,3H), 2.80 (t, 2H), 3.31 (bt, 2H), 6.59 (dd, 1H), 6.88 (d, 1H), 7.09 (d,1H); MS(ES+): m/z 188 (M−NH₂)⁺(ES−): m/z 203 (M−H)⁻;

l) 6-Fluoro-5-methoxytryptamine;

m) 5,6-Difluorotryptamine;

n) 6-Chloro-5-fluorotryptamine;

o) 5-Trifluoromethoxytryptamine;

p) 4,6-Difluoro-5-methoxytryptamine;

q) 4-Phenyltryptamine;

r) 6-Phenyltryptamine;

s) 5-Isopropyltryptamine;

t) 4,6-Difluoro-5-methoxy-1-methyltryptamine: ¹H NMR (300 MHz, CDCl₃):3.0 (m, 4H), 3.67 (s, 3H), 3.98 (s, 3H), 6.85 (m, 2H); and

u) 4,6-Difluoro-5-methoxy-1-methyltryptamine: ¹H NMR (300 MHz, d6-DMSO):2.92 (t, 2H), 3.39 (t, 2H), 3.69 (s, 3H), 6.75 (m, 1H), 7.13 (m, 2H);MS(ES+): m/z 211; (M+H)⁺ 194 (M−NH₂)⁺.

EXAMPLE 53 4-Methoxytryptamine hydrochloride

Dissolve 4-methoxytryptamine (1 g, 5.26 mmol) in MeOH and add of NH₄Cl(0.97 eq, 0.27 g, 5.10 mmol). After 30 minutes, evaporate in vacuo toremove the MeOH leaving a thick orange oil. Dissolve the oil in MeOH andadd dropwise to Et₂O (200 mL) with vigorous stirring giving a gummywhite precipitate. Stir with heating to give the title compound as asolid: ¹H NMR (d₆-DMSO, 300 MHz): 3.06 (bs, 4H); 3.86 (s, 3H); 6.46 (dd,1H); 7.06-6.9 (m, 3H); 7.93 (bs, 1H); 10.9 (s, 1H); MS (ES+): m/z 191(M+H)⁺; 175 (M−CH₃)⁺; 174 (M−NH₂)⁺; (ES−): 189 (M−H)⁻; Analysis forC₁₁H₁₅ClN₂O: Calcd.: C, 58.2788; H, 6.6692; N, 12.3566; found C, 58.18;H, 6.73; N, 12.15.

EXAMPLE 54 5,6-Difluorotryptamine hydrochloride

Prepare by the method of Example 53 to give the title compound: ¹H NMR(300 MHz, d6-DMSO): 2.97 (m, 4H), 7.27 (m, 1H), 7.36 (m, 1H), 7.53 (m,1H), 11.20 (bs, 1H); MS(ES+): m/z 197 (M+H)⁺, 180 (M−NH₂)⁺; (ES−): m/z195 (M−H)⁻.

EXAMPLE 55 4-Phenyltryptamine hydrochloride

Add a solution of HCl (4.6 mL of 4 M HCl in 1,4-dioxane) dropwise to asolution of 4-phenyltryptamine (3.33 g, 14.09 mmol) in EtOAc/Et₂O togive a solid. Collect the solid by filtration and dry overnight in avacuum oven at room temperature to give the title compound as an offwhite solid: ¹H NMR (300 MHz, d6-DMSO): 2.54 (m, 4H), 6.82 (m, 1H), 7.14(t, 1H), 7.27 (m, 1H), 7.41 (m, 5H), 7.68 (bs, 2H), 11.28 (bs, 1H);MS(ES+): m/z 237 (M+H)⁺, 220 (M−NH₂)⁺; (ES−): m/z 235 (M−H)⁻; Analysisfor C₁₆H₁₇ClN₂; Calcd.; C, 70.4517; H, 6.2818; N, 10.2696; found; C,70.26; H, 6.16; N, 10.20.

EXAMPLE 56 5-Chloro-6-fluorotryptamine hydrochloride

Prepare by the method of Example 55 to give the title compound: ¹H NMR(300 MHz, d6-DMSO): 3.00 (m, 4H), 7.37 (m, 1H), 7.53 (d, 1H), 7.59 (d,1H), 11.28 (bs, 1H); MS(ES+): m/z 213 (M+H)⁺, 196, 198 (M−NH₂)⁺; (ES−):m/z 211, 213 (M−H)⁻.

EXAMPLE 57 4-Chlorotryptamine oxalate

Add dropwise oxalic acid (1.32 g, 1.3 eq.) in MeOH to a solution of4-chlorotryptamine in EtOAc (2.2 g, 11.3 mmol) with vigorous stirring.When addition was complete, add Et₂O to the cloud point and place flaskin the freezer to give a solid. Collect the solid by filtration and washwith ether. Dry in a vacuum oven at room temperature to give the titlecompound as an off-white solid: ¹H NMR (300 MHz, d6-DMSO): 3.11 (m, 2H),3.2 (m, 2H), 7.04 (m, 2H), 7.34 (m, 2H), 11.44 (bs, 1H); MS (ES+): m/z195 (M+H)⁺, 178 (M−NH₂)⁺; (ES−): m/z 193 (M−H)⁻; Analysis forC₁₂H₁₃ClN₂O₄: Calcd.: C, 50.6263; H, 4.6026; N, 9.8396; found: C, 50.56;H, 4.57; N, 9.66.

Using the method of Example 57 gives the following compounds: a)6-Phenyltryptamine oxalate: 3.05 (m, 4H), 7.31 (m, 3H), 7.45 (t, 2H),7.65 (m, 4H), 11.10 (bs, 1H). MS(ES+): m/z 237 (M+H)⁺, 220 (M−NH₂)⁺;(ES−): m/z 235 (M−H)⁻;

b) 4,6-Difluoro-5-methoxytryptamine oxalate: ¹H NMR (300 MHz, d6-DMSO):3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H), 7.22 (m, 1H), 11.29 (bs, 1H);MS(ES+): m/z 227 (M+H)⁺; (ES−): m/z 225 (M−H)⁻; Analysis forC₁₃H₁₄F₂N₂O₅: Calcd.; C, 49.3718; H, 4.4620; N, 8.8576; found; C, 49.68;H, 4.57; N, 8.60; and

c) 5-Isopropyltryptamine oxalate: ¹H NMR (300 MHz, d6-DMSO): 1.25 (d,6H), 3.01 (m, 4H), 6.99 (m, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.36 (bs,1H), 10.85 (bs, 1H); MS(ES+): m/z 203 (M+H)⁺, 186 (M−NH₂)⁺; (ES−): m/z201 (M−H)⁻.

EXAMPLE 58 5-Trifluoromethoxytryptamine oxalate

Add oxalic acid (1.3 eq.) in acetone to a solution of5-trifluoromethoxytryptamine in acetone. Warm and add Et₂O to the cloudpoint and then placed in the freezer overnight to obtain the titlecompound as a white crystalline solid: ¹H NMR (300 MHz, d6-DMSO): 3.02(m, 4H), 7.06 (m, 1H), 7.39 (m, 1H), 7.45 (d, 1H), 7.55 (m, 1H), 11.30(bs, 1H). MS(ES+): m/z 245 (M+H)⁺, 228 (M−NH₂)⁺; (ES−): m/z 243 (M−H)⁻;Analysis for C₁₁H₁₁F₃N₂O: Calcd.; C, 46.7144; H, 3.9203; N, 8.3809;found; C, 46.55; H, 3.62; N, 8.27.

Using the method of Example 58 gives the following compounds: a)4,6-Difluoro-5-methoxytryptamine oxalate: ¹H NMR (300 MHz, d6-DMSO):3.04 (m, 4H), 3.85 (s, 3H), 7.10 (m, 1H), 7.22 (m, 1H), 11.29 (bs, 1H);MS(ES+): m/z 227 (M+H)⁺; (ES−): m/Z 225 (M−H)⁻; Analysis forC₁₃H₁₄F₂N₂O₅: Calcd.; C, 49.3718; H, 4.4620; N, 8.8576; found; C, 49.68;H, 4.57; N, 8.60.

EXAMPLE 60 4-Fluorotryptamine oxalate

Add dropwise oxalic acid (1.44 g, 1.2 eq.) in acetonitrile to anacetonitrile solution of 4-fluorotryptamine with vigorous stirring. Warmadd MeOH to make a solution. Add Et₂O to the cloud point and cool thesolution in the freezer to give a solid. Collect the solid by filtrationand dry in a vacuum oven overnight at 45° C. to give the title compoundas a tan solid: ¹H NMR (300 MHz, d6-DMSO): 3.07 (m, 4H), 6.73 (m, 1H),7.04 (m, 1H), 7.22 (m, 2H), 11.30 (bs, 1H); MS (ES+): m/z 179 (M+H)⁺;(ES−): m/z 177 (M−H)⁻.

EXAMPLE 61 6-Fluoro-5-methoxytryptamine oxalate

Add oxalic acid (3.91 g, 1.2 eq.) in MeOH dropwise to an EtOAc/MeOHsolution of 6-fluoro-5-methoxytryptamine with vigorous stirring. AddEt₂O to give a solid and collect the solid by filtration and dryovernight in a vacuum oven at 60° C. to give the title compound: ¹H NMR(300 MHz, d6-DMSO): 3.0 (m, 4H), 3.85 (s, 3H), 7.21 (m, 3H), 10.89 (bs,1H); MS(ES+): m/z 209 (M+H)⁺; Analysis for C₁₃H₁₅FN₂O₅: Calcd.: C,52.3496; H, 5.0690; N, 9.3919; Found: C, 52.06; H, 4.91; N, 9.20.

EXAMPLE 62 2-(2-(7-Fluoro-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine 2-fluorohydrazine hydrochloride (3.25 g, 20 mmol) and2-(4,4-diethoxy-butyl)-isoindole-1,3-dione (6.99 g, 24 mmol) anddissolve in 4% aqueous H₂SO₄. Heat the reaction to reflux. After 2hours, cool to ambient temperature. Basify the reaction mixture with 30%aqueous NH₄OH to pH of about 11. Extract with dichloromethane (2×100mL). Combine the organic phases, dry over MgSO₄, filter, and remove thesolvent leaving an orange oil. Absorb the oil onto silica gel and loadon top short column of silica gel equilibrated with 15% EtOAc inhexanes. Eluent with 15% EtOAc in hexanes (1500 mL) and then 30% EtOAcin hexanes (2000 mL) to give, after evaporation, the title compound as ayellow solid: ¹H NMR (300 MHz, d6-DMSO): 3.03 (t, 2H), 3.85 (t, 2H),6.91 (m, 2H), 7.25 (m, 1H), 7.36 (d, 1H), 7.83 (m, 4H), 11.32 (bs, 1H);MS (FD): m/z 308 (M+).

EXAMPLE 63 7-Fluorotryptamine oxalate

Dissolve 2-(2-(7-fluoro-1H-indol-3-yl)ethyl)isoindole-1,3-dione in 25 mLof THF. Add ethanolamine (63.4 g, 62.65 mL, 1038 mmol, 100 eq.) withvigorous stirring and heat to 70° C. After 1.5 hours, cool to roomtemperature. After 18 hours, pour reaction mixture into of water (250mL) containing of 5N NaOH (3 mL) and extract with Et₂O (2×200 mL).Combine the organic layers and wash with 0.1 N NaOH. Collect the organiclayer, dry over MgSO₄, filter, and remove the solvent in vacuo to givethe title compound as a yellow oil.

Add oxalic acid (0.62 g, 1.2 eq.) in MeOH dropwise to an EtOAc solutionof the base (1.02 g, 5.72 mmol) with vigorous stirring. Heat the cloudysuspension to reflux for 30 minutes and then cool to give a solid.Collect the solid by filtration and dry overnight in a vacuum oven at60° C. to give the title compound as an off-white solid: ¹H NMR (300MHz, d6-DMSO): 3.04 (m, 4H), 6.96 (m, 2H), 7.30 (m, 1H), 7.38 (d, 1H),11.51 (bs, 1H); MS (ES+): m/z 179 (M+H)⁺, 162 (M−NH₂)⁺; (ES−): m/z 177(M−H)⁻; Analysis for C₁₂H₁₃FN₂O₄: Calcd.: C, 53.7318; H, 4.8849; N,10.4431; found: C, 53.50; H, 4.86; N, 10.32.

EXAMPLE 64 6-Trifluoromethyltryptamine oxalate

Add 6-trifluoromethyltryptamine to 1:1 acetone/Et₂O. Add dropwise ofoxalic acid (1.2 eq.) in acetone to give a solid. Collect the solid byfiltration and dry overnight in the vacuum oven to obtain the titlecompound: MS(ES+): m/z 212 (M−NH₂)⁺; (ES−): m/z 227 (M−H)⁻.

EXAMPLE 65 4,6-Difluoro-5-methoxy-1H-indole

Dissolve 2,6-difluoro-4-nitrophenol (J. Heterocyclic. Chem. 1976, 13,1253; 10 g, 57.11 mmol) in 300 mL of benzene. Add dropwise a solution of1-methyl-3-p-tolyltriazene (9.37 g, 62.82 mmol, 1.1 eq.) in benzene (150mL). After TLC indicates absence of starting material, transfer thereaction mixture to a separator funnel and wash with 1 N HCl, thensaturated NaHCO₃, and then water. Dry the organic layer over MgSO₄,filter, and remove the solvent to give a residue. Crystallize theresidue from MeOH/water to give 1,3-difluoro-2-methoxy-5-nitrobenzene aswhite needles: ¹H NMR (300 MHz, CDCl₃): 4.25 (t, 3H), 7.80 (d, 2H).

Combine 1,3-difluoro-2-methoxy-5-nitrobenzene (10.12 g, 53.51 mmol) and4 chlorophenoxyacetonitrile (11.21 g, 66.89 mmol, 1.25 eq.) in DMSO (150mL). Add dropwise to a suspension of solid NaOH (powdered, 10.70 g,267.55 mmol, 5 eq.) over 5 hours. After 18 hours, pour the reactionmixture into cold, aqueous HCl and extract with Et₂O (2×150 mL). Combinethe organic layers, wash with brine, and evaporate to give a residue.Chromatograph the residue on silica gel and eluting with 20% EtOAc inhexanes to give, after evaporation,(2,4-difluoro-3-methoxy-6-nitrophenyl)acetonitrile as a yellow oil:MS(ES−): m/z 227 (M−H)⁻.

Using (2,4-difluoro-3-methoxy-6-nitrophenyl)acetonitrile in thecyclization as described in Israel J. Chem. 1966, 4, 155-159 gives anoil. Chromatograph the oil on silica gel eluting with 20% EtOAc inhexanes to give, after evaporation, the title compound as a purplesolid; ¹H NMR (300 MHz, d6-DMSO): 3.85 (bs, 3H), 6.46 (m, 1H), 7.12 (d,1H), 7.36 (m, 1H), 11.35 (bs, 1H); MS(ES−): m/z 182 (M−H)⁻.

Using the method of Example 65 gives the following compounds: a)4,6-Difluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃): 4.68 (d, 2H), 6.14 (m,2H), 6.57 (bs, 2H); MS(ES+): m/z 205, 207 (M+H)⁺ which gives the titlecompound.

EXAMPLE 66 4,6-Difluoro-5-methoxy-1-methyl-1H-indole

Combine 4,6-difluoro-5-methoxy-1H-indole (7.5 g, 40.95 mmol) and coldDMF (100 mL) and treat with NaH (1.8 g, 45.05 mmol, 1.1 eq.) and withvigorously stirring. After about 10 minutes, add dropwise iodomethane(11.62 g, 81.90 mmol, 2 eq.). After the addition was complete, allow thereaction to stir at room temperature for several hours until TLCindicates the absence of starting material. Dilute the reaction withwater and extract with Et₂O (2×150 mL). Combine the organic layers, dryover MgSO₄, filter, and remove the solvent leaving an oil. Chromatographthe oil on silica gel eluting with 10% EtOAc in hexanes to give, afterevaporation, the title compound as a light yellow oil: ¹H NMR (300 MHz,CDCl₃): 3.72 (s, 3H), 3.97 (s, 3H), 6.50 (d, 1H), 6.84 (d, 1H), 6.98 (d,1H); MS(ES+): m/z 198 (M+H)⁺; Analysis for C₁₀H₉F₂NO: Calcd.: C, 60.91;H, 4.60; N, 7.10; found: C, 60.93; H, 4.63; N, 7.25.

Using the method of Example 66 gives the following compounds: a)4,6-Difluoro-1-methyl-1H-indole.

EXAMPLE 67 N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

Combine 3-phenoxybenzaldehyde (5.6 ml, 26.7 mmol), 5-methoxytryptamine(5.0 g, 26.7 mmol) and 3 Å molecular sieves (1.0 g) in methanol (50 ml)and under argon and heat at reflux for 4 hours. Remove the molecularsieves by filtration and then slowly add sodium borohydride (3.0 g, 60.0mmol) portionwise. Stir at room temperature for 1 hour and concentrateunder reduced pressure, dissolve the concentrated reaction mixture insodium hydroxide 1N (100 ml) and extract with dichloromethane (3×50 ml).Combine organic layers and wash sequentially with distilled water (50ml) and brine (50 ml), dry (Na₂SO₄) the organic layer, and concentrateto give a residue. Chromatograph the residue on silica gel eluting with9:1 EtOAc:MeOH with 2% NH4OH gives the title compound.

Formation of oxalate salt: Add a solution of the free base (8.7 g, 23.5mmol) in EtOAc (50 ml) to a solution of oxalic acid (2.1 g, 23.5 mmol)in EtOAc (5 ml) to give a precipitate. Collect the precipitate andrecrystallize from methanol/diethyl ether to give a solid. Collect thesolid by filtration, rinse with diethyl ether, and dry in a vacuum ovenat 50° C. overnight to give the title compound as the oxalate, mp188-190° C., RMN consistent, Mass: m/z 373.2 (M+), Anal. Calcd forC₂₆H₂₆N₂O₆: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.38; H, 5.46; N,6.04.

By the method of Example 67 the following compounds were prepared,isolated as the oxalate except where noted:

No. Z′ X R₄ Data  68 H —O— phenyl mp 203-205° C., Mass: m/z 343.1 (M⁺),Anal. Calcd for C₂₅H₂₄N₂O₅: C, 69.43; H, 5.59; N, 6.48 Found: C, 69.25;H, 5.42; N, 6.37  69 H —S— phenyl mp 106-108° C., Mass: m/z 359.2 (M⁺),Anal. Calcd for C₂₂H₂₄N₂O₄S: C, 66.95; H, 5.39; N, 6.25 Found: C, 66.19;H, 5.49; N, 6.13  70 H —SO₂— phenyl mp 203-205° C., Mass: m/z 391.2(M⁺), Anal. Calcd for C₂₅H₂₄N₂O₆S: C, 62.49; H, 5.03; N, 5.83 Found: C,62.05; H, 5.21; N, 5.82  71 5-methoxy —S— phenyl mp 198-200° C., Mass:m/z 389.3 (M⁺), Anal. Calcd for C₂₆H₂₆N₂O₅S: C, 65.25; H, 5.48; N, 5.85Found: C, 64.50; H, 5.63; N, 5.73  72 5-methoxy —SO₂— phenyl mp 142-144°C., Mass: m/z 421.1 (M⁺), Anal. Calcd for C₂₆H₂₆N₂O₇S: C, 61.16; H,5.13; N, 5.49 Found: C, 61.14; H, 5.38; N, 5.25  73 H —S— 4- mp 190-192°C., Mass: m/z 373.2 methylphenyl (M⁺), Anal. Calcd for C₂₆H₂₆N₂O₄S: C,67.51; H, 5.67; N, 6.06 Found: C, 67.44; H, 5.69; N, 6.13  74 H —SO₂—4-methyl mp 212-214° C., Mass: m/z 405.4 phenyl (M⁺), Anal. Calcd forC₂₆H₂₆N₂O₆S: C, 63.14; H, 5.30; N, 5.66 Found: C, 62.59; H, 5.70; N,5.29  75 5-methoxy —CH(F)— phenyl mp 214-216° C., Mass: m/z 389.3 (M⁺),Anal. Calcd for C₂₇H₂₇FN₂O₅: C, 67.77; H, 5.69; N, 5.85 Found: C, 67.52;H, 5.77; N, 5.64  76 H —CH(F)— phenyl mp 216-218° C., Mass: m/z 359.2(M⁺), Anal. Calcd for C₂₆H₂₅FN₂O₄: C, 69.63; H, 5.62; N, 6.25 Found: C,69.55; H, 5.36; N, 5.95  77 5-methoxy —CH₂— phenyl mp 199-202° C., Mass:m/z 371.1 (M⁺), Anal. Calcd for C₂₇H₂₈N₂O₅: C, 70.42; H, 6.13; N, 6.08Found: C, 69.73; H, 6.25; N, 6.05  78 H —CH₂— phenyl mp 222-224° C.,Mass: m/z 341.2 (M⁺), Anal. Calcd for C₂₆H₂₆N₂O₄: C, 72.54; H, 6.09; N,6.51 Found: C, 72.23; H, 6.08; N, 6.37  79 5-methoxy —CH(OH)— phenyl mp146-148, Mass: m/z 387.2, Anal. Calcd for C₂₇H₂₈N₂O₅: C, 68.05; H, 5.92;N, 5.88 Found: C, 67.29; H, 6.03; N, 5.51  80 H —CH(OH)— phenyl mp167-169° C., Mass: m/z 357.3 (M⁺), Anal. Calcd for C₂₆H₂₆N₂O₅: C, 69.94;H, 5.87; N, 6.27. Found: C, 68.11; H, 6.07; N, 6.06  81 5-methoxy —NH—phenyl mp 170-172° C., Mass: m/z 372.3 (M⁺), Anal. Calcd for C₂₆H₂₇N₃O₅:C, 67.67; H, 5.90; N, 9.10 Found: C, 67.24; H, 6.08; N, 8.54  82 H —NH—phenyl mp 196-198° C., Mass: m/z 342.2 (M⁺), Anal. Calcd for C₂₅H₂₅N₃O₄:C, 69.59; H, 5.84; N, 9.74 Found: C, 67.57; H, 6.06; N, 8.84  835-methoxy —NH— benzyl mp 203-205° C., Mass: m/z 386.2 (M⁺), Anal. Calcdfor C₂₇H₂₉N₃O₅: C, 68.20; H, 6.15; N, 8.84 Found: C, 67.46; H, 6.14; N,8.79  84 H —NH— benzyl mp 204-206° C., Mass: m/z 356.3 (M⁺), Anal. Calcdfor C₂₆H₂₇N₃O₄: C, 70.10; H, 6.11; N, 9.43. Found: C, 68.48; H, 5.95; N,9.26.  85 5-methoxy —O— H mp 126-128° C., Mass: m/z 297.5 (M⁺), Anal.Calcd for C₁₈H₂₀N₂O₂: C, 72.94; H, 6.80; N, 9.45. Found: C, 71.78; H,6.71; N, 9.20. (isolated as the base)  86 H —O— H mp 143-145° C., Mass:m/z 267.3 (M⁺), Anal. Calcd for C₁₇H₁₈N₂O: C, 76.66; H, 6.81; N, 10.51.Found: C, 75.11; H, 6.61; N, 10.22 (isolated as the base)  87 5-fluoro—O— phenyl mp 204-206° C., Mass: m/z 361.1 (M⁺), Anal. Calcd forC₂₅H₂₃FN₂O₅: C, 66.66; H, 5.15; N, 6.22. Found: C, 66.83; H, 5.17; N,6.30.  88 5-methoxy —O— naphth-1-yl mp 196-198° C., Mass: m/z 423.1(M⁺), Anal. Calcd for C₃₀H₂₆N₂O₆: C, 70.30; H, 5.51; N, 5.47. Found: C,68.11; H, 5.56; N, 5.52.  89 H —O— naphth-1-yl mp 210-212° C., Mass: m/z393.2 (M⁺), Anal. Calcd for C₂₉H₂₄N₂O₅: C, 72.19; H, 5.43; N, 5.81.Found: C, 72.10; H, 5.40; N, 6.66.  90 5-methoxy —O— 3-fluoro mp186-188° C., Mass: m/z 391.2 phenyl (M⁺), Anal. Calcd for C₂₆H₂₅FN₂O₆:C, 64.99; H, 5.24; N, 5.83. Found: C, 63.10; H, 5.11; N, 5.67.  91 H —O—3-fluoro mp 217-219° C. in 75% yield, RMN phenyl consistent, Mass: m/z361.1 (M⁺), Anal. Calcd for C₂₅H₂₃FN₂O₅: C, 66.66; H, 5.15; N, 6.22.Found: C, 66.12; H, 5.22; N, 6.34.  92 5-methoxy —O— 2-fluoro mp184-186° C., Mass: m/z 391.2 phenyl (M⁺), Anal. Calcd for C₂₆H₂₅FN₂O₆:C, 64.99; H, 5.24; N, 5.83. Found: C, 65.06; H, 5.23; N, 5.85.  93 H —O—2-fluoro mp 206-208° C., Mass: m/z 361.1 phenyl (M⁺), Anal. Calcd forC₂₅H₂₃FN₂O₅: C, 66.66; H, 5.15; N, 6.22. Found: C, 66.30; H, 4.97; N,6.21.  94 5-methoxy —O— 4-fluoro mp 184-186° C., Mass: m/z 391.2 phenyl(M⁺), Anal. Calcd for C₂₆H₂₅FN₂O₆: C, 64.99; H, 5.24; N, 5.83. Found: C,63.99; H, 4.95; N, 5.75.  95 H —O— 4-fluoro mp 222-224° C., Mass: m/z361.1 phenyl (M⁺), Anal. Calcd for C₂₅H₂₃FN₂O₅: C, 66.66; H, 5.15; N,6.22. Found: C, 65.74; H, 4.81; N, 6.13.  96 5-methoxy —O— naphth-2-ylmp 198-200° C., Mass: m/z 423.1 (M⁺), Anal. Calcd for C₃₀H₂₆N₂O₆: C,70.30; H, 5.51; N, 5.47. Found: C, 68.97; H, 5.43; N, 5.44.  97 H —O—naphth-2-yl mp 219-221° C., Mass: m/z 393.2 (M⁺), Anal. Calcd forC₂₉H₂₄N₂O₅: C, 72.19; H, 5.43; N, 5.81. Found: C, 71.65; H, 5.32; N,5.91.  98 5-methoxy —O— benzyl mp 204-206° C., Mass: m/z 387.2 (M⁺),Anal. Calcd for C₂₇H₂₈N₂O₆: C, 68.05; H, 5.92; N, 5.87. Found: C, 67.26;H, 5.80; N, 5.86.  99 H —O— benzyl mp 211-213° C., Mass: m/z 357.3 (M⁺),Anal. Calcd for C₂₆H₂₆N₂O₅: C, 69.94; H, 5.86; N, 6.27. Found: C, 69.46;H, 5.75; N, 6.16. 100 5-hydroxy —O— phenyl mp 188-190° C., Mass: m/z359.2 (M⁺), Anal. Calcd for C₂₅H₂₄N₂O₆: C, 66.95; H, 5.39; N, 6.24.Found: C, 63.56; H, 5.01; N, 5.86. 101 5-methoxy —O— pyrimid-5-yl mp191-193° C., Mass: m/z 375.2 (M⁺), Anal. Calcd for C₂₄H₂₄N₄O₆: C, 62.06;H, 5.20; N, 12.06. Found: C, 61.66; H, 5.41; N, 10.87. 102 H —O—pyrimid-5-yl mp 188-190° C., Mass: m/z 345.1 (M⁺), Anal. Calcd forC₂₃H₂₂N₄O₅: C, 63.58; H, 5.10; N, 12.89. Found: C, 62.52; H, 5.28; N,11.58. 103 5-methoxy —O— pyrid-4-yl mp 124-126° C., Mass: m/z 374.2(M⁺), Anal. Calcd for C₂₃H₂₅Cl₂N₃O₂: C, 61.88; H, 5.64; N, 9.41. Found:C, 61.26; H, 5.70; N, 9.14. (isolated as the hydrochloride) 104 H —O—pyrid-4-yl mp 147-149° C., Mass: m/z 344.2 (M⁺), Anal. Calcd forC₂₂H₂₃Cl₂N₃O: C, 63.46; H, 5.56; N, 10.09. Found: C, 61.47; H, 5.33; N,9.43. (isolated as the hydrochloride) 105 6-chloro —O— pyrid-4-yl mp150-152° C., Mass: m/z 378.2 (M⁺), Anal. Calcd for C₂₂H₂₂Cl₃N₃O: C,58.61; H, 4.91; N, 9.32. Found: C, 57.28; H, 4.61; N, 8.85. 1065-methoxy —O— pyrid-3-yl mp 178-180° C., Mass: m/z 374.2 (M⁺), Anal.Calcd for C₂₅H₂₅N₃O₆: C, 64.78; H, 5.43; N, 9.06. Found: C, 63.02; H,5.30; N, 8.87. 107 H —O— pyrid-3-yl mp 190-192° C., Mass: m/z 344.1(M⁺), Anal. Calcd for C₂₄H₂₃N₃O₅: C, 66.50; H, 5.34; N, 9.69. Found: C,65.69; H, 5.21; N, 9.20. 108 5-fluoro —O— pyrid-3-yl mp 135-137° C.,Mass: m/z 362.3 (M⁺), Anal. Calcd for C₂₂H₂₂Cl₂FN₃O: C, 60.83; H, 5.10;N, 9.67. Found: C, 61.49; H, 5.31; N, 9.70. (isolated as thehydrochloride) 109 6-chloro —O— pyrid-3-yl mp 160-162° C., Mass: m/z378.1 (M⁺), Anal. Calcd for C₂₂H₂₂Cl₃N₃O: C, 58.61; H, 4.91; N, 9.32.Found: C, 58.18; H, 4.89; N, 9.01. (isolated as the hydrochloride) 1105-methoxy —O— pyrid-2-yl mp 202-204° C., Mass: m/z 374.2 (M⁺), Anal.Calcd for C₂₃H₂₅Cl₂N₃O₂: C, 61.88; H, 5.64; N, 9.41. Found: C, 60.57; H,6.35; N, 10.89. (isolated as the hydrochloride) 111 H —O— pyrid-2-yl mp196-198° C., Mass: m/z 344.2 (M⁺), Anal. Calcd for C₂₂H₂₃Cl₂N₃O: C,63.46; H, 5.56; N, 10.09. Found: C, 63.69; H, 6.09; N, 11.62. (isolatedas the hydrochloride) 112 6-chloro —O— pyrid-2-yl mp 149-151° C., Mass:m/z 378.1 (M⁺), Anal. Calcd for C₂₂H₂₂Cl₃N₃O: C, 58.61; H, 4.91; N,9.32. Found: C, 61.96; H, 4.91; N, 9.73. (isolated as the hydrochloride)113 5-methoxy —O— thiazol-2-yl mp 180-182° C., Mass: m/z 380.3 (M⁺),Anal. Calcd for C₂₃H₂₃N₃O₆S: C, 58.83; H, 4.93; N, 8.94. Found: C,58.11; H, 4.79; N, 8.84. 114 H —O— thiazol-2-yl mp 203-205° C., Mass:m/z 350.3 (M⁺), Anal. Calcd for C₂₂H₂₁N₃O₅S: C, 60.12; H, 4.81; N, 9.56.Found: C, 59.73; H, 4.83; N, 9.36. 115 5-methoxy —O— 2,6-difluoro mp137-139° C., Mass: m/z 473.1 phenylsulfonyl (M⁺) Anal. Calcd forC₂₆H₂₄F₂N₂O₈S: C, 55.51; H, 4.30; N, 4.97. Found: C, 55.90; H, 4.47; N,5.12. 116 H —O— 2,6-difluoro mp 185-187° C., Mass: m/z 443.2phenylsulfonyl (M⁺), Anal. Calcd for C₂₅H₂₂F₂N₂O₇S: C, 56.38; H, 4.16;N, 5.26. Found: C, 56.96; H, 4.39; N, 5.31. 117 5-methoxy —NH—pyrid-2-yl mp 174-176° C., Mass: m/z 373.1 (M⁺), Anal. Calcd forC₂₃H₂₆Cl₂N₄O₆: C, 62.02; H, 5.88; N, 12.57. Found: C, 61.45; H, 5.91; N,12.22. (isolated as the hydrochloride) 118 H —NH— pyrid-2-yl mp 168-170°C., Mass: m/z 343.1 (M⁺), Anal. Calcd for C₂₂H₂₄Cl₂N₄: C, 63.61; H,5.82; N, 13.48. Found: C, 62.18; H, 6.12; N, 12.11. (isolated as thehydrochloride) 119 6-chloro —NH— pyrid-2-yl mp 164-166° C., Mass: m/z377.1 (M⁺), Anal. Calcd for C₂₂H₂₃Cl₃N₄: C, 58.74; H, 5.15; N, 12.45.Found: C, 57.75; H, 5.07; N, 11.94. (isolated as the hydrochloride) 1205-methoxy —NH— pyrid-3-yl mp 150-154° C., Mass: m/z 373.2 (M⁺) Anal.Calcd for C₂₃H₂₆Cl₂N₄O₆: C, 62.02; H, 5.88; N, 12.57. Found: C, 61.30;H, 6.58; N, 10.87. (isolated as the hydrochloride) 121 H —NH— pyrid-3-ylmp 140-142° C., Mass: m/z 343.2 (M⁺), Anal. Calcd for C₂₂H₂₂N₄: C,77.16; H, 6.47; N, 16.36. Found: C, 75.73; H, 6.54; N, 15.58. (isolatedas the base) 122 6-chloro —NH— pyrid-3-yl mp 172-174° C., Mass: m/z377.2 (M⁺), Anal. Calcd for C₂₂H₂₃Cl₃N₄: C, 58.74; H, 5.15; N, 12.45.Found: C, 57.05; H, 5.16; N, 11.84. (isolated as the hydrochloride) 1235-methoxy —NH— pyrid-4-yl mp 170-172° C., Mass: m/z 373.3 (M⁺), Anal.Calcd for C₂₃H₂₆Cl₂N₄O₆: C, 62.02; H, 5.88; N, 12.57. Found: C, 61.05;H, 6.08; N, 11.97. (isolated as the hydrochloride) 124 H —NH— pyrid-4-ylmp 174-176° C., Mass: m/z 343.4 (M⁺), Anal. Calcd for C₂₂H₂₄Cl₂N₄: C,63.61; H, 5.82; N, 13.48. Found: C, 62.32; H, 6.20; N, 12.44. (isolatedas the hydrochloride) 125 6-chloro —NH— pyrid-4-yl mp 158-160° C., Mass:m/z 377.2 (M⁺), Anal. Calcd for C₂₂H₂₃Cl₃N₄: C, 58.74; H, 5.15; N,12.45. Found: C, 57.17; H, 5.19; N, 11.69. (isolated as thehydrochloride) 126 5-methoxy- —NH— 2,2,2- mp 151-153° C., Mass: m/z397.2 6-fluoro trifluoroethyl (M⁺), Anal. Calcd for C₂₄H₂₄F₄N₂O₆: C,56.25; H, 4.72; N, 5.46. Found: C, 56.38; H, 4.76; N, 5.53. (isolated asthe maleate) 127 5-methoxy- —NH— 2,2,3,3,3- mp 145-147° C., Mass: m/z447.2 6-fluoro pentafluoro (M⁺), Anal. Calcd for propyl C₂₅H₂₄F₆N₂O₆: C,53.38; H, 4.30; N, 4.98. Found: C, 53.36; H, 4.29; N, 5.00. (isolated asthe maleate) 128 5-methoxy- —O— 2,2,3,3- mp 143-145° C., Mass: m/z 429.26-fluoro tetrafluoro (M⁺), Anal. Calcd for propyl C₂₅H₂₅F₅N₂O₆: C,55.14; H, 4.62; N, 5.14. Found: C, 55.10; H, 4.62; N, 5.18. (isolated asthe maleate) 129 5-methoxy —C(O)— phenyl mp 163-166°, Mass: m/z 385.2(M⁺), Anal. Calcd for C₂₇H₂₆N₂O₆: C, 68.34; H, 5.52; N, 5.90. Found: C,66.64; H, 5.56; N, 5.90. 130 H —C(O)— phenyl mp 168-170° C., Mass: m/z355.3 (M⁺), Anal. Calcd for C₂₆H₂₄N₂O₅: C, 70.26; H, 5.44; N, 6.30.Found: C, 69.51; H, 5.52; N, 6.22. 130 6-fluoro —O— pyrid-4-yl mp:123.4-124.9° C. Mass (ES+): A m/z 363.0 (M + 1). Anal. Calcd. forC₂₂H₂₀FN₃O: C, 73.11; H, 5.58; N, 11.63. Found: C, 73.36; H, 5.41; N,11.57. (isolated as the free base) 130 6-fluoro —O— pyrid-3-yl mp169.0-170.8° C. Mass (APCI): B m/z 362.1 (M + 1). Anal. Calcd forC₂₂H₂₀F₁N₃O.1.0 C₄H₄O₄: C, 65.40; H, 5.07; N, 8.80. Found: C, 65.45; H,5.12; N, 8.70. (isolated as the maleate salt) 130 5-methoxy —O— 2,2,2trifluoro mp 151-153° C. Mass: m/z 397.2 C 6-fluoro ethyl (M⁺), Anal.Calcd for C₂₄H₂₄F₄N₂O₆: C, 56.25; H, 4.72; N, 5.46. Found: C, 56.38; H,4.76; N, 5.53. (isolated as the maleate salt)

By the method of Example 67 the following compounds were prepared,isolated as late except where noted:

No. Z′ X R₄ Data 131 3-chloro —O— phenyl mp 222-224° C., Mass: m/z 338.2(M⁺), Anal. Calcd for C₂₃H₂₂ClNO₅: C, 64.56; H, 5.18; N, 3.27. Found: C,64.24; H, 5.02; N, 3.89. 132 3-trifluoro —O— phenyl mp 220-222° C.,Mass: m/z 372.2 methyl (M⁺), Anal. Calcd for C₂₄H₂₂F₃NO₅: C, 62.47; H,4.81; N, 3.04. Found: C, 62.69; H, 4.78; N, 3.10. 133 4-methoxy —O—phenyl mp 221-223° C., Mass: m/z 334.2 (M⁺), Anal. Calcd for C₂₄H₂₅NO₆:C, 68.07; H, 5.95; N, 3.31. Found: C, 67.98; H, 5.92; N, 3.29. 134 3,4-—O— phenyl Mp 209-211° C., Mass: m/z 364.2 dimethoxy (M⁺), Anal. Calcdfor C₂₅H₂₇N₇: C, 66.21; H, 6.00; N, 3.09. Found: C, 66.28; H, 6.07; N,3.27. 135 3-methoxy —O— phenyl Mp 210-212° C., Mass: m/z 334.1 (M⁺),Anal. Calcd for C₂₄H₂₅NO₆: C, 68.07; H, 5.95; N, 3.31. Found: C, 68.31;H, 5.78; N, 3.36. 136 3,4- —O— phenyl mp 219-221° C., Mass: m/z 372.1dichloro (M⁺), Anal. Calcd for C₂₃H₂₁Cl₂NO₅: C, 59.75; H, 4.58; N, 3.03.Found: C, 58.98; H, 4.63; N, 3.66. 137 3-chloro —O— 3- mp 214-216° C.,Mass: m/z 406.4 trifluoromethyl (M⁺), Anal. Calcd for phenylC₂₄H₂₁ClF₃NO₅: C, 58.13; H, 4.27; N, 2.82. Found: C, 58.28; H, 4.53; N,2.86. 138 3-chloro —O— 4-t-butyl mp 221-223° C., Mass: m/z 394.2 phenyl(M⁺), Anal. Calcd for C₂₇H₃₀ClNO₅: C, 67.00; H, 6.25; N, 2.89. Found: C,66.36; H, 5.83; N, 2.94. 139 3-chloro —O— 4-chloro mp 212-214° C., Mass:m/z 372.1 phenyl (M⁺), Anal. Calcd for C₂₃H₂₁Cl₂NO₅: C, 59.75; H, 4.58;N, 3.03. Found: C, 61.50; H, 4.77; N, 3.20. 140 3-chloro —O— 4-methoxymp 207-209° C., Mass: m/z 368.2 phenyl (M⁺), Anal. Calcd forC₂₄H₂₄ClNO₆: C, 62.95; H, 5.28; N, 3.06. Found: C, 63.17; H, 5.32; N,3.19. 141 3-chloro —O— 4-methyl mp 206-208° C., Mass: m/z 352.4 phenyl(M⁺), Anal. Calcd for C₂₄H₂₄ClNO₅: C, 65.23; H, 5.47; N, 3.17. Found: C,67.52; H, 5.68; N, 3.30. 142 3-chloro —O— 3,5-dichloro mp 223-225° C.,Mass: m/z 406.3 phenyl (M⁺), Anal. Calcd for C₂₃H₂₀Cl₃NO₅: C, 55.61; H,4.06; N, 2.82. Found: C, 56.08; H, 3.83; N, 2.26. 143 3-chloro —O—3,4-dichloro mp 217-219° C., Mass: m/z 406.4 phenyl (M⁺), Anal. Calcdfor C₂₃H₂₀Cl₃NO₅: C, 55.61; H, 4.06; N, 2.82. Found: C, 55.73; H, 4.38;N, 3.02. 144 H —O— phenyl mp 162-164° C., Mass: m/z 304.2 (M⁺), Anal.Calcd for C₂₃H₂₃NO₅: C, 70.22; H, 5.89; N, 3.56. Found: C, 70.70; H,5.38; N, 3.78. 145 4-chloro —O— phenyl mp 222-224° C., Mass: m/z 338.2(M⁺), Anal. Calcd for C₂₃H₂₂ClNO₅: C, 64.56; H, 5.18; N, 3.27. Found: C,63.65; H, 5.18; N, 3.25. 146 3-chloro —S— phenyl mp 122-124° C., Mass:m/z 354.3 (M⁺), Anal. Calcd for C₂₃H₂₂ClNO₄S: C, 62.23; H, 4.99; N,3.15. Found: C, 63.08; H, 5.09; N, 3.15. 147 3-chloro —SO₂— phenyl mp110-112° C., Mass: m/z 386.1 (M⁺), Anal. Calcd for C₂₃H₂₂ClNO₆S: C,58.04; H, 4.66; N, 2.94. Found: C, 58.91; H, 4.78; N, 3.05. 148 H —S—phenyl mp 111-113° C., Mass: m/z 320.1 (M⁺), Anal. Calcd for C₂₃H₂₃NO₄S:C, 67.46; H, 5.66; N, 3.42. Found: C, 67.66; H, 5.77; N, 3.41. 149 H—SO₂— phenyl mp 127-129° C., Mass: m/z 352.4 (M⁺), Anal. Calcd forC₂₃H₂₃NO₆S: C, 62.57; H, 5.25; N, 3.17. Found: C, 62.75; H, 5.16; N,3.26. 150 3-chloro —S— 4-methyl mp 222-224° C., Mass: m/z 368.1 phenyl(M⁺), Anal. Calcd for C₂₄H₂₄ClNO₄S: C, 62.94; H, 5.28; N, 3.06. Found:C, 63.11; H, 5.35; N, 3.11. 151 3-chloro —SO₂— 4-methyl mp 226-228° C.,Mass: m/z 400.1 phenyl (M⁺), Anal. Calcd for C₂₄H₂₄ClNO₆S: C, 58.83; H,4.94; N, 2.86. Found: C, 58.79; H, 4.94; N, 2.93. 152 3-chloro —NH—benzyl mp 206-208° C., Mass: m/z 351.5 (M⁺), Anal. Calcd forC₂₄H₂₅ClN₂O₄: C, 65.38; H, 5.72; N, 6.35. Found: C, 65.23; H, 5.86; N,6.29. 153 3-chloro —NH— phenyl mp 196-198° C., Mass: m/z 337.2 (M⁺),Anal. Calcd for C₂₃H₂₃ClN₂O₄: C, 64.71; H, 5.43; N, 6.56. Found: C,56.60; H, 4.90; N, 5.64. 154 3-chloro —CH(OH)— phenyl mp 193-195° C.,Mass: m/z 352.4 (M⁺), Anal. Calcd for C₂₄H₂₄ClN₂O₅: C, 65.23; H, 5.47;N, 3.17. Found: C, 64.96; H, 5.60; N, 3.32. 155 3-chloro —CH₂— phenyl mp220-222° C., Mass: m/z 336.1 (M⁺), Anal. Calcd for C₂₄H₂₄ClNO₄: C,67.68; H, 5.68; N, 3.29. Found: C, 67.65; H, 5.83; N, 3.42. 156 3-chloro—CH(F)— phenyl mp 182-184° C., Mass: m/z 354.3 (M⁺), Anal. Calcd forC₂₄H₂₃ClFNO₄: C, 64.94; H, 5.22; N, 3.16. Found: C, 65.21; H, 5.26; N,3.09. 157 3-chloro —O— 4-fluoro mp 218-220° C., Mass: m/z 356.2 phenyl(M⁺), Anal. Calcd for C₂₃H₂₁ClFNO₅: C, 61.96; H, 4.75; N, 3.14. Found:C, 60.56; H, 4.67; N, 3.17. 158 3-trifluroro —O— 4-fluoro mp 221-223°C., Mass: m/z 390.2 methyl phenyl (M⁺), Anal. Calcd for C₂₄H₂₁F₄NO₅: C,60.13; H, 4.42; N, 2.92. Found: C, 59.18; H, 4.30; N, 2.91. 159 3-chloro—O— 2-fluoro mp 214-216° C., Mass: m/z 356.2 phenyl (M⁺), Anal. Calcdfor C₂₃H₂₁ClFNO₅: C, 61.96; H, 4.75; N, 3.14. Found: C, 61.42; H, 4.68;N, 3.21. 160 3-trifluroro —O— 2-fluoro mp 218-220° C., Mass: m/z 390.2methyl phenyl (M⁺), Anal. Calcd for C₂₄H₂₁F₄NO₅: C, 60.13; H, 4.42; N,2.92. Found: C, 59.83; H, 4.34; N, 2.96. 161 3-chloro —O— 3-fluoro mp219-221° C., Mass: m/z 356.2 phenyl (M⁺), Anal. Calcd for C₂₃H₂₁ClFNO₅:C, 61.96; H, 4.75; N, 3.14. Found: C, 61.26; H, 4.74; N, 3.11. 1623-trifluroro —O— 3-fluoro mp 221-223° C., Mass: m/z 390.2 methyl phenyl(M⁺), Anal. Calcd for C₂₄H₂₁F₄NO₅: C, 60.13; H, 4.42; N, 2.92. Found: C,58.79; H, 4.28; N, 2.88. 163 3-chloro —O— naphth-2-yl mp 229-231° C.,Mass: m/z 388.1 (M⁺), Anal. Calcd for C₂₇H₂₄ClNO₅: C, 67.85; H, 5.06; N,2.93. Found: C, 67.71; H, 5.02; N, 3.03. 164 3-trifluroro —O—naphth-2-yl mp 225-227° C., Mass: m/z 422.0 methyl (M⁺), Anal. Calcd forC₂₈H₂₄F₃NO₅: C, 65.75; H, 4.73; N, 2.74. Found: C, 65.72; H, 4.84; N,2.88. 165 3-chloro —O— naphth-1-yl mp 208-210° C., Mass: m/z 388.1 (M⁺),Anal. Calcd for C₂₇H₂₄ClNO₅: C, 67.85; H, 5.06; N, 2.93. Found: C,66.71; H, 5.11; N, 3.26. 166 3-trifluroro —O— naphth-1-yl mp 211-213°C., Mass: m/z 422.0 methyl (M⁺), Anal. Calcd for C₂₈H₂₄F₃NO₅: C, 65.75;H, 4.73; N, 2.74. Found: C, 64.30; H, 4.76; N, 2.90. 167 3-chloro —O— Hmp 96-98° C., Mass: m/z 262.0 (M⁺), Anal. Calcd for C₁₅H₁₅ClNO: C,68.83; H, 6.16; N, 5.35. Found: C, 68.59; H, 5.99; N, 5.37. (isolated asthe base) 168 3-trifluroro —O— H mp 101-103° C., Mass: m/z 296.3 methyl(M⁺), Anal. Calcd for C₁₆H₁₆F₃NO: C, 65.07; H, 5.46; N, 4.74. Found: C,65.06; H, 5.42; N, 4.80. (isolated as the base) 169 3-trifluroro —O—benzyl mp 223-225° C., Mass: m/z 386.1 methyl (M⁺), Anal. Calcd forC₂₅H₂₄F₃NO₅: C, 63.15; H, 5.08; N, 2.94. Found: C, 63.22; H, 4.97; N,3.02. 170 3-chloro —O— 2,4-difluoro mp 201-203° C., Mass: m/z 438.0phenylsulfonyl (M⁺), Anal. Calcd for C₂₃H₂₀ClF₂NO₇S: C, 52.32; H, 3.81;N, 2.65. Found: C, 52.26; H, 3.80; N, 2.71. 171 3-trifluroro —O—2,4-difluoro mp 202-204° C., Mass: m/z 472.2 methyl phenylsulfon- (M⁺),Anal. Calcd for yl C₂₄H₂₀F₅NO₇S: C, 51.34; H, 3.59; N, 2.49. Found: C,51.61; H, 3.65; N, 2.54. 172 3-chloro —O— thiazol-2-yl mp 216-218° C.,Mass: m/z 345.0 (M⁺), Anal. Calcd for C₂₀H₁₉ClN₂O₅S: C, 55.23; H, 4.40;N, 6.44. Found: C, 55.15; H, 4.16; N, 6.43. 173 3-trifluroro —O—thiazol-2-yl mp 222-224° C., Mass: m/z 379.4 methyl (M⁺), Anal. Calcdfor C₂₁H₁₉F₃N₂O₅S: C, 53.84; H, 4.08; N, 5.98. Found: C, 53.71; H, 3.95;N, 5.96. 174 3-chloro —O— pyrid-3-yl mp 213-215° C., Mass: m/z 339.1(M⁺), Anal. Calcd for C₂₂H₂₁ClN₂O₅: C, 61.61; H, 4.93; N, 6.53. Found:C, 60.40; H, 4.89; N, 6.74. 175 3-trifluroro —O— pyrid-3-yl mp 221-223°C., Mass: m/z 373.1 methyl (M⁺), Anal. Calcd for C₂₃H₂₁F₃N₂O₅: C, 59.74;H, 4.57; N, 6.05. Found: C, 59.17; H, 4.47; N, 6.93. 176 3-methoxy —O—pyrid-3-yl mp 101-103° C., Mass: m/z 335.2 (M⁺), Anal. Calcd forC₂₁H₂₄Cl₂N₂O₂: C, 61.92; H, 5.93; N, 6.87. Found: C, 61.43; H, 6.07; N,6.25. (isolated as the hydrochloride) 177 3-chloro —O— pyrid-4-yl mp154-156° C., Mass: m/z 339.1 (M⁺), Anal. Calcd for C₂₀H₂₁Cl₃N₂O: C,58.34; H, 5.14; N, 6.80. Found: C, 58.35; H, 5.18; N, 6.69. (isolated asthe hydrochloride) 178 3-trifluoro —O— pyrid-4-yl mp 208-210° C., Mass:m/z 373.1 methyl (M⁺), Anal. Calcd for C₂₁H₂₁Cl₂F₃N₂O: C, 56.64; H,4.75; N, 6.29. Found: C, 56.57; H, 4.68; N, 6.20. (isolated as thehydrochloride) 179 3-chloro —O— pyrimid-5-yl mp 205-207° C., Mass: m/z340.1 (M⁺), Anal. Calcd for C₂₁H₂₀ClN₃O₅: C, 58.67; H, 4.68; N, 9.77.Found: C, 57.66; H, 4.70; N, 8.17. 180 3-trifluoro —O— pyrimid-5-yl mp218-220° C., Mass: m/z 374.1 methyl (M⁺), Anal. Calcd for C₂₂H₂₀F₃N₃O₅:C, 57.02; H, 4.35; N, 9.06. Found: C, 56.55; H, 4.44; N, 8.89. 1813-chloro —O— pyrid-2-yl mp 93-95° C., Mass: m/z 339.1 (M⁺), Anal. Calcdfor C₂₀H₂₁Cl₃N₂O: C, 58.34; H, 5.14; N, 6.80. Found: C, 62.31; H, 5.30;N, 7.36. (isolated as the hydrochloride) 182 3-trifluoro —O— pyrid-2-ylmp 86-88° C., Mass: m/z 373.1 (M⁺), methyl Anal. Calcd forC₂₁H₂₁Cl₂F₃N₂O: C, 56.64; H, 4.75; N, 6.29. Found: C, 60.00; H, 4.92; N,6.76. (isolated as the hydrochloride) 183 3-chloro —NH— pyrid-3-yl mp158-160° C., Mass: m/z 338.3 (M⁺), Anal. Calcd for C₂₂H₂₂ClN₃O₄: C,61.75; H, 5.18; N, 9.82. Found: C, 58.90; H, 4.64; N, 8.87. 1843-trifluroro —NH— pyrid-3-yl mp 182-184° C., Mass: m/z 372.3 methyl(M⁺), Anal. Calcd for C₂₃H₂₂F₃N₃O₄: C, 59.86; H, 4.80; N, 9.10. Found:C, 58.33; H, 4.44; N, 8.60. 185 3-chloro —NH— pyrid-4-yl mp 156-158° C.,Mass: m/z 338.3 (M⁺), Anal. Calcd for C₂₀H₂₂Cl₃N₃: C, 58.48; H, 5.39; N,10.22. Found: C, 57.13; H, 5.49; N, 9.80. (isolated as thehydrochloride) 186 3-trifluroro —NH— pyrid-4-yl mp 142-144° C., Mass:m/z 372.3 methyl (M⁺), Anal. Calcd for C₂₁H₂₂Cl₂F₃N₃: C, 56.76; H, 4.99;N, 9.45. Found: C, 55.05; H, 4.88; N, 9.33. (isolated as thehydrochloride) 187 3-chloro —NH— pyrid-2-yl mp 142-144° C., Mass: m/z338.0 (M⁺), Anal. Calcd for C₂₀H₂₂Cl₃N₃: C, 58.48; H, 5.39; N, 10.22.Found: C, 58.12; H, 5.39; N, 10.08. (isolated as the hydrochloride) 1883-trifluroro —NH— pyrid-2-yl mp 144-146° C., Mass: m/z 372.1 methyl(M⁺), Anal. Calcd for C₂₁H₂₂Cl₂F₃N₃: C, 56.76; H, 4.99; N, 9.45. Found:C, 56.60; H, 5.04; N, 9.32. (isolated as the hydrochloride) 189 3-chloro—O— benzyl MS m/e 351.9 (m + 1) 190 3-trifluroro —NH— phenyl mp =205-207° C.; ms: m + 1 = 371.1 methyl

By the method of Example 67 the following compounds were prepared,isolated as late except where noted:

No. R₁ Data 191 pyrid-4-yl mp 176-178° C., Mass: m/z 305.2 (M⁺), Anal.Calcd for C₂₂H₂₂N₂O₅: C, 66.99; H, 5.62; N, 7.10. Found: C, 67.55; H,5.70; N, 7.24. 192 pyrid-3-yl mp 198-200° C., Mass: m/z 305.2 (M⁺),Anal. Calcd for C₂₂H₂₂N₂O₅: C, 66.99; H, 5.62; N, 7.10. Found: C, 64.98;H, 5.43; N, 6.86. 193 thien-2-yl mp 234-236° C., Mass: m/z 310.2 (M⁺),Anal. Calcd for C₂₁H₂₁NO₅S: C, 63.14; H, 5.29; N, 3.50. Found: C, 62.25;H, 5.18; N, 3.53. 194 imidazol-4-yl mp 194-196° C., Mass: m/z 294.2(M⁺), Anal. Calcd for C₂₀H₂₀N₃O₅: C, 62.65; H, 5.52; N, 10.95. Found: C,59.94; H, 5.30; N, 10.12. 195 naphth-2-yl mp 223-225° C., Mass: m/z354.4 (M⁺), Anal. Calcd for C₂₇H₂₅NO₅: C, 73.12; H, 5.68; N, 3.16.Found: C, 73.38; H, 5.94; N, 3.40. 196 naphth-1-yl mp 223-225° C., Mass:m/z 354.4 (M⁺), Anal. Calcd for C₂₇H₂₅NO₅: C, 73.12; H, 5.68; N, 3.16.Found: C, 73.18; H, 5.52; N, 3.23.

By the method of Example 67 the following compounds were prepared,isolated as late except where noted:

No. R₁ Data 197 3-chlorophenyl mp 240-242° C., Mass: m/z 336.0 (M⁺),Anal. Calcd for C₂₃H₂₀ClNO₅: C, 55.23; H, 4.40; N, 6.44. Found: C,55.15; H, 4.16; N, 6.43. 198 3-trifluoromethyl mp 255-257° C., Mass: m/z370.0 (M⁺), Anal. Calcd for phenyl C₂₄H₂₀F₃NO₅: C, 62.74; H, 4.38; N,3.04. Found: C, 62.95; H, 4.27; N, 3.08. 199 5-methoxy-1H- mp 232-234°C., Mass: m/z 371.1 (M⁺), Anal. Calcd for indol-3-yl C₂₆H₂₄N₂O₆: C,67.81; H, 5.25; N, 6.08. Found: C, 67.46; H, 4.44; N, 5.44. 2001H-indol-3-yl mp 221-223° C., Mass: m/z 341.1 (M⁺), Anal. Calcd forC₂₅H₂₂N₂O₅: C, 69.75; H, 5.15; N, 6.50. Found: C, 71.99; H, 4.48; N,6.40.

By the method of Example 67 the following compounds were prepared,isolated as late except where noted:

No. R₁ R₉ Data 201 3-chlorophenyl phenyl mp 225-227° C., Mass: m/z 361.1(M+), Anal. Calcd for C₂₅H₂₃ClN₂O₄: C, 66.59; H, 5.14; N, 6.21. Found:C, 66.21; H, 5.02; N, 6.14. 202 3-trifluoromethyl phenyl mp 216-218° C.,Mass: m/z 395.1 (M+), Anal. phenyl Calcd for C₂₅H₂₅F₃N₂O₄: C, 64.45; H,4.78; N, 5.78. Found: C, 63.98; H, 4.67; N, 5.76. 203 5-methoxy-1H-phenyl mp 208-210° C., Mass: m/z 394.2 (M+), Anal. indol-3-yl Calcd forC₂₈H₂₇N₃O₅: C, 69.26; H, 5.60; N, 8.62. Found: C, 67.78; H, 5.29; N,8.42. 204 1H-indol-3-yl phenyl mp 227-229° C., Mass: m/z 364.3 (M+),Anal. Calcd for C₂₇H₂₅N₃O₄: C, 71.19; H, 5.53; N, 9.22. Found: C, 70.02;H, 5.33; N, 8.95. 205 5-methoxy-1H- H mp 170-172° C., Mass: m/z 318.2(M+), Anal. indol-3-yl Calcd for C₂₂H₂₃N₃O₅: C, 64.53; H, 5.62; N,10.26. Found: C, 56.16; H, 4.98; N, 8.75.

By the method of Example 67 the following compounds were prepared,isolated as late except where noted:

No. R₁ R₉ Data 206 3-chlorophenyl phenyl mp 237-239° C., Mass: m/z 361.1(M⁺), Anal. Calcd for C₂₅H₂₃ClN₂O₄: C, 66.59; H, 5.14; N, 6.21. Found:C, 66.55; H, 5.16; N, 6.20. 207 3-trifluoromethyl phenyl mp 239-241° C.,Mass: m/z 395.1 (M⁺), Anal. phenyl Calcd for C₂₅H₂₅F₃N₂O₄: C, 64.45; H,4.78; N, 5.78. Found: C, 64.59; H, 4.83; N, 5.83. 208 5-methoxy-1H-phenyl mp 194-196° C., Mass: m/z 396.2 (M⁺), Anal indol-3-yl Calcd forC₂₈H₂₇N₃O₅: C, 69.26; H, 5.60; N, 8.62. Found: C, 68.33; H, 5.37; N,8.52. 209 1H-indol-3-yl phenyl mp 206-208° C., Mass: m/z 366.2 (M⁺),Anal. Calcd for C₂₇H₂₅N₃O₄: C, 71.19; H, 5.53; N, 9.22. Found: C, 69.23;H, 5.42; N, 8.86. 210 5-methoxy-1H- H mp 186-188° C., Mass: m/z 318.2(M⁺), Anal. indol-3-yl Calcd for C₂₂H₂₃N₃O₅: C, 64.53; H, 5.66; N,10.26. Found: C, 62.88; H, 4.61; N, 9.27.

EXAMPLE 220 N-(2-(3-Chlorophenyl)ethyl)-3-benzoylbenzylamine

Combine 3-benzoylbenzaldehyde (0.45 g, 2.1 mmol), and(3-chlorophenyl)ethylamine (0.3 ml, 2.1 mmol) and 3 Å molecular sieves(1.0 g) in MeOH (30 ml). Heat to reflux. After 3 hours, cool, filter,and concentrate to give a residue. Dissolve the residue indichloroethane (20 ml), add acetic acid (0.12 ml, 2.1 mmol) and sodiumtriacetoxyborohydride (0.6 g, 2.94 mmol) and stir at ambienttemperature. After 2 hours, concentrate the reaction mixture and adddichloromethane (90 ml) and extract sequentially with distilled water(50 ml) and then brine (50 ml). Dry the organic layer over Na₂SO₄ andgive a residue. Chromatograph the residue on silica gel eluting withEtOAc to give the title compound as the base.

The oxalate using the method of Example 67 to give the title compound:mp 196-198° C., Mass: m/z 350.4 (M+), Anal. Calcd for C₂₄H₂₂ClNO₅: C,65.53; H, 5.04; N, 3.18. Found: C, 65.27; H, 5.20; N, 3.13.

EXAMPLE 221 N-(2-(3-Chlorophenyl)ethyl)-3-ethoxybenzylamine

Combine 3-ethoxybenzaldehyde (3.38 g, 22.5 mmol),2-(3-chlorophenyl)ethylamine (2.33 g, 15.0 mol), and 3 Å molecularsieves (2.88 g) in ethanol (230 ml). Stir the reaction mixture at refluxfor 4 hours. Filter to remove the molecular sieves and then slowly addsodium borohydride (1.70 g, 45.0 mmol) to the filtrate and stir atambient temperature. After 15 hours, concentrate the reaction mixture toa residue, dissolve the residue in 1 N NaOH, and extract withdichloromethane. Combine organic extracts, wash with brine, dry overNa₂SO₄, and concentrate to a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate to give the title compound. TheHCl salt was prepared in ethyl acetate to give the title compound: mp178-180° C.; MS (ACPI): m/e 290.1 (M+1); Analysis for C₁₇H₂₁Cl₂NO:Calcd: C, 62.58; H, 6.49; N, 4.29; Found: C, 62.65; H, 6.53; N, 4.32.

By the method of Example 221 the following compounds were prepared,isolated as the maleate except where noted:

No. Z″ R₄ Data 222 3-chloro propyl mp 138-140° C. MS (ACPI): m/e 304.1(M + 1). Analysis for C₁₈H₂₃Cl₂NO: Calcd: C, 63.53; H, 6.81; N, 4.12;found: C, 63.74; H, 6.81; N, 4.22. (isolated as the hydrochloride) 2233- propyl mp 145-147° C. MS (ACPI): m/e 338.1 (M + 1). trifluoroAnalysis for C₂₃H₂₆F₃NO₅: Calcd: C, 60.92; H, methyl 5.78; N, 3.09;found: C, 60.77; H, 5.60; N, 3.12. 224 3- ethyl mp 164-166° C. MS(ACPI): m/e 324.2 (M + 1). trifluoro Analysis for C₁₈H₂₁ClF₃NO: Calcd:C, 60.09; H, methyl 5.88; N, 3.89; found: C, 60.42; H, 5.80; N, 3.93.(isolated as the hydrochloride) 225 2-phenyl 2,2,2-trifluoro mp 181-183°C. MS (ACPI): m/e 386.2 (M + 1). ethyl Analysis for C₂₇H₂₆F₃NO₅: Calcd:C, 64.67; H, 5.23; N, 2.79; found: C, 64.52; H, 5.01; N, 2.85. 2264-phenyl 2,2,2-trifluoro mp 39° C. MS (ACPI): m/e 386.2 (M + 1). ethyl(Exception- one equivalent of triethylamine in the reaction) (isolatedas the free base)

By the method of Example 221 the following compounds were prepared,isolated as the maleate except where noted:

No. Z′ R₄ Data 227 5-chloro ethyl mp 153-156° C., MS (ACPI): m/e 329.1(M + 1). Analysis for C₂₃H₂₅ClN₂O₅: Calcd: C, 62.09; H, 5.66; N, 6.30;found: C, 62.27; H, 5.38; N, 6.19 228 5-chloro propyl mp 163-166° C. MS(ACPI): m/e 343.1 (M + 1). Analysis for C₂₄H₂₇ClN₂O₅: Calcd: C, 62.81;H, 5.93; N, 6.10; found: C, 63.07; H, 5.80; N, 6.07. 229 5-chloro 2,2,2-mp 178-181° C., MS (ACPI): m/e 383.1 (M + 1). trifluoroethyl Analysisfor C₂₃H₂₂ClF₃N₂O₅: Calcd: C, 55.37; H, 4.44; N, 5.62; found: C, 55.71;H, 4.39; N, 5.66. 230 5-chloro 3-fluoropropyl mp 167-170° C., MS (ACPI)m/e 361.1 (M + 1). Analysis for C₂₄H₂₆ClFN₂O₅: Calcd: C, 60.44; H, 5.49;N, 5.87; found: C, 60.30; H, 5.25; N, 5.78. 231 5-chloro 2,2,3,3,3- mp170-173° C. MS (ACPI) m/e 433.1 (M + 1). pentafluoro Analysis forC₂₄H₂₂ClF₅N₂O₅: Calcd: C, 52.52; H, propyl 4.04; N, 5.10; found: C,52.49; H, 4.06; N, 5.16. 232 5-chloro 2,2,3,3- mp 163-167° C., MS (ACPI)m/e 415.1 (M + 1). tetrafluoro Analysis for C₂₄H₂₃ClF₄N₂O₅: Calcd: C,54.30; H, propyl 4.37; N, 5.28; found: C, 54.47; H, 4.36; N, 5.33. 2335- 2,2,2- mp 179-182° C., MS (ACPI): m/e 379.1 (M + 1). methoxytrifluoroethyl Analysis for C₂₄H₂₅F₃N₂O₆: Calcd: C, 58.30; H, 5.10; N,5.67; found: C, 58.26; H, 5.09; N, 5.69. 234 6-chloro 2,2,3,3- mp156-160° C., MS (ACPI): m/e 415.1 (M + 1). tetrafluoro Analysis forC₂₄H₂₃ClF₄N₂O₅: Calcd: C, 54.30; H, propyl 4.37; N, 5.28; found: C,54.31; H, 4.34; N, 5.31. 235 5-cyano 2,2,2- mp 176-178° C. MS (ACPI) m/e374.0 (M + 1). trifluoroethyl Analysis for C₂₀H₁₉ClF₃N₃₀: Calcd: C,58.61; H, 4.67; N, 10.25; found: C, 58.52; H, 4.61; N, 10.17. (isolatedas the hydrochloride) 236 5-methyl 2,2,2-trifluoro mp 193-195° C. MS(ACPI) m/e 429.9 (M + 1). sulfonyl ethyl Analysis for C₂₄H₂₅F₃N₂O₇S:Calcd: C, 53.13; H, 4.64; N, 5.16; found: C, 53.12; H, 4.58; N, 5.20.237 5-cyano 3,3,3-trifluoro mp 150-154° C. MS (ACPI): m/e 387.9 (M + 1).propyl Analysis for C₂₅H₂₄F₃N₃O₅: Calcd: C, 59.64; H, 4.80; N, 8.35;found: C, 59.55; H, 4.77; N, 8.38. 238 5-methyl 3,3,3-trifluoro mp178-181° C. MS (ACPI): m/e 440.9 (M + 1). sulfonyl propyl Analysis forC₂₅H₂₇F₃N₂O₇S: Calcd: C, 53.95; H, 4.89; N, 5.03; found: C, 53.87; H,4.86; N, 5.04. 239 4-fluoro 2,2,2-trifluoro mp 199-202° C. MS (ACPI) m/e367.2 (M + 1). ethyl Analysis for C₁₉H₁₉ClF₄N₂O: calcd: C, 56.65; H,4.75; N, 6.95; found: C, 56.82; H, 4.65; N, 6.84. (isolated as thehydrochloride) 240 4-fluoro 2,2,3,3,3- mp 118-121° C. MS (ACPI): m/e417.2 (M + 1). pentafluoro Analysis for C₂₄H₂₂F₆N₂O₅: Calcd: C, 54.14;H, propyl 4.16; N, 5.26; found: C, 54.39; H, 4.25; N, 5.30. 241 4-fluoro2,2,3,3- mp 188-191° C. MS (ACPI) m/e 399.0 (M + 1). tetrafluoroAnalysis for C₂₀H₂₀ClF₅N₂O: Calcd: C, 55.24; H, propyl 4.64; N, 6.44;found: C, 55.03; H, 4.53; N, 6.34. (isolated as the hydrochloride) 2427-fluoro 2,2,2-trifluoro mp 157-160° C. MS (ACPI) m/e 367.2 (M + 1).ethyl Analysis for C₂₃H₂₂F₄N₂O₅: Calcd: C, 57.26; H, 4.60; N; 5.81;found: C, 57.34; H, 4.39; N, 6.11. 243 7-fluoro 2,2,3,3,3- mp 166-168°C. MS (ACPI): m/e 417.2 (M + 1). pentafluoro Analysis for C₂₄H₂₂F₆N₂O₅:Calcd: C, 54.14; H, propyl 4.16; N, 5.26; found: C, 53.99; H, 3.98; N,5.61. 244 7-fluoro 2,2,3,3- mp 170-173° C. MS (ACPI): m/e 399.2 (M + 1).tetrafluoro Analysis for C₂₄H₂₄F₅N₂O₅: Calcd: C, 56.03; H, propyl 4.51;N, 5.45; found: C, 55.73; H, 4.30; N, 5.66. 245 5-amido 3,3,3-trifluoromp 143-147° C. MS (ACPI): m/e 406.1 (M + 1). propyl Analysis forC₂₁H₂₂F₃N₃O₂: Calcd: C, 62.22; H, 5.47; N, 10.36; found: C, 61.96; H,5.42; N, 10.13. (isolated as the base) 246 5-amido 2,2,2-trifluoro mp125-130° C. MS (ACPI) m/e 392.1 (M + 1). ethyl Analysis forC₂₀H₂₁ClF₃N₃O₂: Calcd: C, 56.15; H, 4.95; N, 9.82; found: C, 55.80; H,4.93; N, 9.71. (isolated as the hydrochloride) 247 6-phenyl2,2,2-trifluoro mp 117-120° C. MS (ACPI): m/e 425.1 (M + 1). ethylAnalysis for C₂₄H₂₃F₃N₂O: Calcd: C, 70.74; H, 5.46; N, 6.60; found: C,70.75; H, 5.42; N, 6.66. (isolated as the base) 248 6-methyl 2,2,3,3,3-m.p. 168-170° C. MS (ACPI): m/e 413.2 (M + 1). pentafluoro Analysis forC₂₁H₂₂F₅N₂O: Calcd: C, 56.82; H, propyl 4.77; N, 5.30; found: C, 57.21;H, 4.46; N, 5.33 249 6-phenyl 2,2,3,3,3- mp 110.5-113.5° C. MS (ACPI):m/e 475.1 pentafluoro (M + 1). Analysis for C₂₆H₂₃F₅N₂O: Calcd: C,propyl 65.82; H, 4.89; N, 5.90; found: C, 65.70; H, 4.84; N, 5.93.(isolated as the base) 250 6-phenyl 2,2,3,3- mp 94-98° C. MS (ACPI): m/e457.1 (M + 1). tetrafluoro Analysis for C₂₆H₂₄F₄N₂O: calcd: C, 68.41; H,propyl 5.30; N, 6.14; found: C, 68.18; H, 5.28; N, 6.06 (isolated as thebase) 251 6-methyl 2,2,2-trifluoro mp 176-178° C. MS (ACPI): m/e 363.1(M + 1). ethyl Analysis for C₂₀H₂₂ClF₃N₂O: Calcd: C, 60.23; H, 5.56; N,7.02; found: C, 60.16; H, 5.43; N, 6.98. (isolated as the hydrochloride)252 6-methyl 2,2,3,3- mp 156-158° C. MS (ACPI): m/e 395.1 (M + 1).tetrafluoro Analysis for C₂₁H₂₃ClF₄N₂O: Calcd: C, 58.54; H, propyl 5.38;N, 6.50; found: C, 58.60; H, 5.32; N, 6.55. (isolated as thehydrochloride). 253 6-ethoxy 2,2,3,3- mp 166-168° C. MS (ACPI): m/e453.1 (M + 1). carbonyl tetrafluoro Analysis for C₂₃H₂₅ClF₄N₂O₃: Calcd:C, 56.50; H, propyl 5.15; N, 5.73; found: C, 56.18; H, 5.00; N, 5.66.(isolated as the hydrochloride) 254 6-ethoxy 2,2,2-trifluoro mp169.5-171.5° C. MS (ACPI): m/e 421.2 (M + 1). carbonyl ethyl Analysisfor C₂₆H₂₇F₃N₂O₇: Calcd: C, 58.21; H, 5.07; N, 5.22; found: C, 58.43; H,4.85; N, 5.27. 255 6-cyano 2,2,2-trifluoro mp 175-177° C. MS (ACPI) m/e374.1 (M + 1). ethyl Analysis for C₂₄H₂₂F₃N₃O₅: Calcd: C, 58.90; H,4.53; N, 8.59; found: C, 58.62; H, 4.48; N, 8.50. 256 6-cyano 2,2,3,3-mp 167-169° C. MS (ACPI) m/e 406.1 (M + 1). tetrafluoro Analysis forC₂₅H₂₃F₄N₃O₅: Calcd: C, 57.58; H, propyl 4.45; N, 8.06; found: C, 57.31;H, 4.35; N, 8.08. 257 6-amido 2,2,2- mp 102° C. MS (ACPI) m/e 392.2 (M +1). tetrafluoro Analysis for C₂₀H₂₀F₃N₃O₂: Calcd: C, 61.38; H, ethyl5.15; N, 10.74; found: C, 61.68; H, 5.11; N, 10.65. (isolated as thebase) 258 6-amido 2,2,3,3- mp 120° C. MS (ACPI): m/e 424.3 (M + 1).tetrafluoro Analysis for C₂₁H₂₁F₄N₃O₂: Calcd: C, 59.57; H, propyl 5.00;N, 9.92; found: C, 59.33; H, 4.82; N, 9.79. (isolated as the base) 2596- 2,2,3,3- mp 132-134° C. MS (ACPI): m/e 465.1 (M + 1). trifluorotetrafluoro Analysis for C₂₁H₂₀ClF₇N₂O₂: Calcd: C, 50.36; H, methoxypropyl 4.03; N, 5.59; found: C, 50.25; H, 3.96; N, 5.58. (isolated asthe hydrochloride) 260 6- 2,2,2-trifluoro mp 160-164° C. MS (ACPI): m/e433.1 (M + 1). trifluoro ethyl Analysis for C₂₀H₁₉ClF₆N₂O₂: Calcd: C,51.24; H, methoxy 4.08; N, 5.98; found: C, 51.26; H, 3.99; N, 5.96.(isolated as the hydrochloride) 260A 7-chloro 2,2,3,3- mp 153.6-154.4°C. MS (APCI): m/e 415.1 tetrafluoro (M + 1). Anal. Calcd. forC₂₀H₁₉ClF₄N₂O.1.0HCl: propyl C, 53.23; H, 4.47; N, 6.21. Found: C,52.89; H, 4.40; N, 6.18. (isolated as the hydrochloride) 260B 7-chloro2,2,2- mp 193.4-194.9° C. Mass (ES+): m/z 383.17 trifluoroethyl (M + 1).Anal. Calcd. for C₁₉H₁₈ClF₃N₂O.1.0HCl: C, 54.43; H, 4.57; N, 6.68.Found: C, 54.66; H, 4.39; N, 6.66. (isolated as the hydrochloride)

EXAMPLE 261N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride

Add acetyl chloride (2.4 mL, 33.8 mmol) dropwise to anhydrous ethanol(50 mL) and stir the solution for 10 min at ambient temperature and addto a solution ofN-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine(12.0 g, 30.1 mmol) in ethyl acetate. Concentrate the resulting solutionunder reduced pressure to give a yellow solid. Recrystallize the yellowsolid from ethyl acetate/ethanol/diethyl ether to give the titlecompound: nip 142-143° C. MS(m/e): 399 (M+1), 397 (M−1). Calculated forC₂₀H₁₉F₅N₂O.HCl: Calcd: C, 55.24; H, 4.64; N, 6.44. Found: C, 55.44; H,4.66; N, 6.46.

EXAMPLE 262(N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride L(+)tartrate

Add L-(+)-tartaric acid (49 mg, 0.33 mmol) and methanol to a solution of(N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine(130 mg, 0.33 mmol) in ethyl acetate. Evaporate the solvent to give agum. Crystallize the gum from diethyl ether/ethyl acetate to give thetitle compound: mp 192-194° C.

EXAMPLE 263N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylaminehydrochloride

Add dropwise acetyl chloride (2.3 mL, 32.4 mmol) to anhydrous ethanol(50 mL) and stir the solution for 10 min at ambient temperature and addto a solutionN-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine(10.7 g, 29.2 mmol) in diethyl ether. Concentrate the resulting solutionunder reduced pressure to give a yellow solid. Recrystallize the yellowsolid from ethyl acetate/methanol to give the title compound: mp163-164° C.; MS(m/e): 367 (M+1), 365 (M−1); Calculated for C₁₉H₁₈F₄N₂OHCl: Calcd: C, 56.65; H, 4.75; N, 6.95. Found: C, 56.45; H, 4.54; N,6.90.

EXAMPLE 264N-(2-(7-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamineL(+)tartrate

Add L-(+)-tartaric acid (295 mg, 1.96 mmol) in methanol to a solution ofN-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine(720 mg, 1.96 mmol) in ethyl acetate. Concentrate under reduced pressurethe resulting solution to give a clear colorless oil. Crystallize theoil from diethyl ether to give the title compound: mp 118-119° C.MS(m/e): 367 (M+1), 365 (M−1). Calculated for C₁₉H₁₈F₄N₂O.C₄H₆O₆: Calcd:C, 53.49; H, 4.68; N, 5.42. Found: C, 53.21; H, 4.55; N, 5.41.

EXAMPLE 270 N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-3-propoxybenzylaminehydrochloride

Combine 3-propoxybenzaldehyde (2.96 g, 18.0 mmol), 5-fluorotryptaminehydrochloride (2.58 g, 12.0 mol), triethylamine (1.15 g), and 3 Åmolecular sieves (2.27 g) in ethanol (200 ml). Stir the reaction mixtureat reflux for 4 hours. Filter to remove the molecular sieves and thenslowly add sodium borohydride (1.36 g, 36.0 mmol) to the filtrate andstir at ambient temperature. After 15 hours, concentrate the reactionmixture to a residue, dissolve the residue in 1 N NaOH, and extract withdichloromethane. Combine organic extracts, wash with brine, dry overNa₂SO₄, and concentrate to a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate yielded 3.31 g of an oil. The HClsalt was prepared in diethyl ether: mp 197-199° C.; MS (ACPI): m/e 327.2(M+1); Analysis for C₂₀H₂₄ClFN₂O: Calcd: C, 66.20; H, 6.67; N, 7.72;found: C, 66.06; H, 6.63; N, 7.76.

By the method of Example 270 the following compounds were prepared,isolated as the maleate except where noted:

No. Z′ R₄ Data 271 5-fluoro ethyl mp 196-198° C., MS (ACPI): m/e 313.1(M + 1). Analysis for C₁₉H₂₂ClFN₂O: Calcd: C, 65.42; H, 6.36; N, 8.03;found: C, 65.48; H, 6.30; N, 8.04. (isolated as the hydrochloride) 2725-trifluoro ethyl mp 156-160° C., MS (ACPI): m/e 363.1 (M + 1). methylAnalysis for C₂₄H₂₅F₃N₂O₅: Calcd: C, 60.25; H, 5.27; N, 5.85; found: C,60.47; H, 5.26; N, 5.79. 273 5-trifluoro propyl mp 169-172° C., MS(ACPI): m/e 377.1 (M + 1). methyl Analysis for C₂₅H₂₇F₃N₂O₅: Calcd: C,60.97; H, 5.53; N, 5.69; found: C, 60.95; H, 5.54; N, 5.70 2745-trifluoro 2,2,2- mp 180-184° C. MS (ACPI): m/e 417.1 (M + 1). methyltrifluoro Analysis for C₂₄H₂₂F₆N₂O₅: Calcd: C, 54.14; H, ethyl 4.16; N,5.26; found: C, 53.99; H, 4.07; N, 5.61. 275 5-trifluoro 3,3,3- mp158-161° C., MS (ACPI): m/e 431.1 (M + 1). methyl trifluoro Analysis forC₂₅H₂₄F₆N₂O₅: Calcd: C, 54.95; H, propyl 4.43; N, 5.13; found: C, 54.84;H, 4.46; N, 5.03. 276 4-methoxy 2,2,3,3- mp 144-147° C. MS (ACPI): m/e411.1 (M + 1). tetrafluoro Analysis for C₂₅H₂₆F₄N₂O₆: Calcd: C, 57.03;H, propyl 4.98; N, 5.32; found: C, 56.84; H, 4.94; N, 5.34. 277 5-cyano2,2,3,3- mp 172-174° C. MS (ACPI): m/e 406.2 (M + 1). tetrafluoroAnalysis for C₂₅H₂₃F₄N₃O₅: Calcd: C, 57.58; H, propyl 4.45; N, 8.06;found: C, 57.91; H, 4.13; N, 8.34. 278 5-cyano 2,2,3,3,3- mp 168-170° C.MS (ACPI): m/e 424.1 (M + 1). pentafluoro Analysis for C₂₅H₂₂F₅N₃O₅:Calcd: C, 55.66; H, propoxy 4.11; N, 7.79; found: C, 55.54; H, 4.16; N,7.71. 279 5-(4- 2,2,3,3- p 161-165° C. MS (ACPI): m/e 475.1 (M + 1).fluorophenyl) tetrafluoro Analysis for C₂₆H₂₄ClF₅N₂O: Calcd: C, 61.12;propyl H, 4.73; N, 5.48; found: C, 61.18; H, 4.64; N, 5.50. (isolated asthe hydrochloride) 280 5-(4- 2,2,3,3,3- (isolated as the hydrochloride)mp 168-171° C. fluorophenyl) pentafluoro MS (ACPI): m/e 493.1 (M + 1).Analysis for propoxy C₂₆H₂₃ClF₆N₂O: Calcd: C, 59.04; H, 4.38; N, 5.30;found: C, 59.15; H, 4.28; N, 5.30. (isolated as the hydrochloride) 2815-phenyl 2,2,3,3- mp 148-151° C. MS (ACPI): m/e 457.1 (M + 1).tetrafluoro Analysis for C₂₆H₂₅ClF₄N₂O: Calcd: C, 63.35; propyl H, 5.11;N, 5.68; found: C, 63.16; H, 4.99; N, 5.67. (isolated as thehydrochloride) 282 5-phenyl 2,2,3,3,3- mp 65-70° C., dec. MS (ACPI): m/e475.1 pentafluoro (M + 1). Analysis for C₂₆H₂₄ClF₅N₂O: Calcd: C, prop61.12; H, 4.73; N, 5.48; found: C, 60.98; H, 4.66; N, 5.41. (isolated asthe hydrochloride) 283 5-(4- 2,2,2- mp 214-216° C. MS (ACPI): m/e 443.1(M + 1). fluorophenyl) trifluoro Analysis for C₂₅H₂₃ClF₄N₂O: Calcd: C,62.70; ethyl H, 4.84; N, 5.85; found: C, 62.47; H, 4.71; N, 5.79.(isolated as the hydrochloride) 284 5-phenyl 2,2,2- mp 171-174° C., dec.MS (ACPI): m/e 425.1 trifluoro (M + 1). Analysis for C₂₅H₂₄ClF₃N₂O:Calcd: C, ethyl 65.15; H, 5.25; N, 6.08; found: C, 65.46; H, 5.17; N,6.10. (isolated as the hydrochloride) 285 4-phenyl 2,2,3,3,3- mp 55° C.,dec. MS (ACPI): m/e 475.1 (M + 1). pentafluoro Analysis forC₂₆H₂₄ClF₅N₂O: Calcd: C, 61.12; propyl H, 4.73; N, 5.48; found: C,61.11; H, 4.83; N, 5.40. (isolated as the hydrochloride) 286 4-phenyl2,2,2- mp 60° C., dec. MS (ACPI): m/e 425.1 (M + 1). trifluoro Analysisfor C₂₅H₂₄ClF₃N₂O: Calcd: C, 65.15; ethyl H, 5.25; N, 6.08; found: C,65.08; H, 5.42; N, 5.93. (isolated as the hydrochloride) 287 4-phenyl2,2,3,3- mp 56° C., dec. MS (ACPI): m/e 457.1 (M + 1). tetrafluoroAnalysis for C₂₆H₂₅ClF₄N₂O: Calcd: C, 63.35; propyl H, 5.11; N, 5.68;found: C, 63.60; H, 5.35; N, 5.48. (isolated as the hydrochloride) 2887-fluoro pyrid-4-yl mp 212-214° C. MS (ACPI): m/e 362.2 (M + 1).(isolated as the oxalate) 289 7-fluoro pyrid-3-yl mp 167-169° C. MS(ACPI): m/e 362.3 (M + 1). (isolated as the oxalate) 299 7-phenyl 2,2,2-mp 116-120° C. MS (ACPI): m/e 425.3 (M + 1). trifluoro Analysis forC₂₉H₂₇F₃N₂O₅: Calcd: C, 64.44; H, ethyl 5.03; N, 5.18; found: C, 64.47;H, 4.96; N, 5.24. 300 7-phenyl 2,2,3,3- mp 108-111° C. MS (ACPI): m/e457.3 (M + 1). tetrafluoro Analysis for C₃₀H₂₈F₄N₂O₅: Calcd: C, 62.93;H, propyl 4.93; N, 4.89; found: C, 63.02; H, 4.91; N, 4.96.

EXAMPLE 301N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-methyl-3-(2,2,3,3-tetrafluoropropoxy)benzylaminemaleate

Add 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (232.6 mg, 0.98 mmol) toa solution of N-(2-(6-chloro-1H-indol-3-yl)ethyl)-N-methylamine (205.6mg, 0.98 mmol) and sodium triacetoxy borohydride (305.3 mg, 1.37 mmol)in dichloroethane (50 ml). Stir at ambient temperature. After 24 hours,evaporate to residue and dissolve the residue in 1N NaOH then extractwith dichloromethane. Combine the organic extracts, washed with brine,dry (Na₂SO₄), filter, and evaporate to a residue. Chromatograph theresidue on silica gel eluting with ethyl acetate to give the titlecompound. The maleate salt was prepared in diethyl ether: mp 125-128° C.MS (ACPI): m/e 429.3 (M+1). Analysis for C₂₅H₂₅ClF₄N₂O₅: Calcd: C,55.10; H, 4.62; N, 5.14; found: C, 55.13; H, 4.59; N, 5.09.

By the method of Example 301 the following compounds were prepared:

No. Z′ R₄ Data 302 5-methoxy 2,2,2-trifluoro mp 144-147° C. MS (ACPI):m/e 393.1 (M + 1). ethyl Analysis for C₂₃H₂₅F₃N₂O₆: Calcd: C, 57.26; H,5.22; N, 5.81; found: C, 56.89; H, 5.16; N, 5.82. (isolated as theoxalate) 303 4-methoxy 2,2,3,3- mp 104-109° C. MS (ACPI): m/e 425.2 (M +1). tetrafluoro Analysis for C₂₄H₂₆F₄N₂O₆: Calcd: C, 56.03; H, propyl5.09; N, 5.45; found: C, 55.85; H, 5.05; N, 5.43. (isolated as theoxalate) 304 4-fluoro 2,2,2-trifluoro mp 199-202° C. MS (ACPI): m/e367.2 (M + 1). ethyl Analysis for C₁₉H₁₉ClF₄N₂O: Calcd: C, 56.65; H,4.75; N, 6.95; found: C, 56.82; H, 4.65; N, 6.84. (isolated as thehydrochloride) 305 6-phenyl 2,2,3,3- mp 94-98° C. MS (ACPI): m/e 457.1(M + 1). tetrafluoro Analysis for C₂₆H₂₄F₄N₂O: Calcd: C, 68.41; H,propyl 5.30; N, 6.14; found: C, 68.18; H, 5.28; N, 6.06. (isolated asthe base)

EXAMPLE 306N-(2-(6-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine

CombineN-(2-(6-ethoxycarbonyl-1H-indol-3-yl)ethyl)-N-(2,2,3,3-tetrafluoropropoxybenzyl)amine(1.09 g, 2.4 mmol) and 2N NaOH (4.8 ml) in ethanol (4.8 ml). Heat toreflux. After 2 hours, cool to ambient temperature, evaporate undervacuum to remove the ethanol, and then neutralize with 5N HCl (1.92 ml)to give a solid. Collect the solid by filtration and dry under vacuum togive the title compound as a white powder: mp 186° C., dec, MS (ACPI):m/e 425.1 (M+1).

EXAMPLE 307N-(2-(6-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

The method of Example 306 gives the title compound:

mp 232-235° C. MS (ACPI): m/e 393.2 (M+1).

EXAMPLE 310 5-Phenoxy-1H-indole

Combine potassium hydroxide (3 g, 0.054 mol) and phenol (15 g, 0.16mol), and heat to 110° C. until the potassium hydroxide is dissolved.Cool the mixture to room temperature and add 5-fluoro-2-nitrotoluene(7.75 g, 0.05 mol) in one aliquot. Heat the reaction mixture to 130° C.for 30 min, cool to room temperature, and then pour into 10% NaOH (200mL). Extract the aqueous solution with ether (2×100 mL), combine theorganic layers and wash with 10% NaOH (2×100 mL), water (2×100 mL), dryover Na₂SO₄ and concentrate in vacuo. Chromatograph on silica geleluting with hexanes/ethyl acetate to give 2-nitro-5-phenoxytoluene as asolid: ¹H NMR (300 MHz, CDCl₃) 2.59 (s, 3H), 6.81-6.85 (m, 2H),7.06-7.09 (m, 2H), 7.22-7.26 (m, 1H), 7.40-7.45 (m, 2H), 8.03-8.06 (m,1H).

Combine 2-nitro-5-phenoxytoluene (1.15 g, 5.0 mmol) andtris(dimethylamino)methane (0.87 g, 6.0 mmol) in 10 mL dry toluene andheat to reflux under nitrogen. After 2 hours, cool the reaction mixtureto room temperature and evaporate the toluene under reduced pressure toform a residue. Dissolve the residue in 15 mL EtOAc, mix with Pd/C (10%,100 mg), stir at room temperature under 1 atmosphere of hydrogen for 1.5days. Filter off catalyst and concentrate the filtrate. Chromatograph onsilica gel eluting with hexanes/EtOAc give the title compound as asolid: ¹H NMR (300 MHz, CDCl₃) 6.49-6.50 (m, 1H), 6.93-7.03 (m, 4H),7.22-7.27 (m, 5H), 8.15 (br, 1H).

By the method of Example 310 the following compounds were prepared: a) 4Tolyloxy)-2-methylnitrobenzene: ¹H NMR (300 MHz, CDCl₃) 2.35 (s, 3H),2.57 (s, 3H), 6.77-6.80 (m, 2H), 6.93-7.03 (m, 2H), 7.18-7.24 (m, 2H),8.00-8.03 (m, 1H);

b) 5-p-Tolyloxy-1H-indole: ¹H NMR (300 MHz, CDCl₃) 2.31 (s, 3H),6.48-6.49 (m, 1H), 6.87-6.96 (m, 3H), 7.07-7.10 (m, 2H), 7.20-7.35 (m,3H), 8.15 (br, 1H);

c) 4-(o-Tolyloxy)-2-methylnitrobenzene: ¹H NMR (400 MHz, CDCl₃) 2.16 (s,3H), 2.57 (s, 3H), 6.50-6.78 (m, 2H), 6.93-7.03 (m, 3H), 7.18-7.35 (m,1H), 8.00-8.03 (m, 1H);

d) 5-o-Tolyloxy-1H-indole: ¹H NMR (400 MHz, CDCl₃) 2.31 (s, 3H),6.45-6.46 (m, 1H), 6.78-6.80 (m, 1H), 6.90-6.00 (m, 2H), 7.01-7.10 (m,2H), 7.13-7.24 (m, 2H), 7.32-7.34 (m, 1H), 8.11 (br, 1H);

e) 4-(m-Tolyloxy)-2-methylintrobenzene: ¹H NMR (300 MHz, CDCl₃) 2.37 (s,3H), 2.60 (s, 3H), 6.80-6.88 (m, 4H), 7.03-7.06 (m, 1H), 7.27-7.32 (m,1H), 8.03-8.06 (m, 1H);

f) 5-m-Tolyloxy-1H-indole: 6.0 g (54%) was obtained (red oil). ¹H NMR(300 MHz, CDCl₃) 2.25 (s, 3H), 6.51-6.52 (m, 1H), 6.76-6.98 (m, 4H),7.14-7.39 (m, 4H), 8.17 (br, 1H);

g) 4-(4-Fluorophenoxy)-2-methylnitrobenzene: ¹H NMR (300 MHz, CDCl₃)2.60 (s, 3H), 6.80-6.82 (m, 2H), 7.03-7.12 (m, 4H), 8.03-8.06 (m, 1H);and

h) 5-(4-Fluorophenoxy)-1H-indole: 2.68 g (26%) was obtained (red oil).¹H NMR (300 MHz, CDCl₃) 6.50-6.52 (m, 1H), 6.91-7.01 (m, 5H), 7.24-7.38(m, 3H), 8.18 (br, 1H). a) 5-p-tolyloxy-1H-indole.

EXAMPLE 311 2-Oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride

Combine 5-phenoxy-indole (1.57 g, 7.5 mmol) and anhydrous ether (35 mL)and add oxalyl chloride (1.07 g, 8.25 mmol) in 8 mL ether. A precipitateforms. Stir the reaction over night. Collect the precipitate, dry invacuo, to give the title compound: ¹H NMR (300 MHz, DMSO-d₆) 6.99-7.15(m, 4H), 7.37-7.42 (m, 2H), 7.60 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=2.4Hz), 8.47 (d, 1H, J=3.2 Hz), 12.49, (br, 1H).

By the method of Example 311 the following compounds were prepared: a)2-Oxo-(5-p-tolyloxy-1H-indol-3-yl)acetyl chloride;

b) 2-Oxo-(5-o-tolyloxy-1H-indol-3-yl)acetyl chloride: ¹H NMR (300 MHz,CDCl₃) 2.83 (s, 3H), 6.86-6.89 (m, 1H), 7.03-7.16 (m, 5H), 7.26-7.27 (m,1H). 7.40-7.44 (m, 1H), 7.87 (m, 1H), 8.20-8.32 (m, 2H), 8.90 (br, 1H);

c) 2-Oxo-(5-n-tolyloxy-1H-indol-3-yl)acetyl chloride; and

d) 2-Oxo-((4-fluorophenoxy)-1H-indol-3-yl)acetyl chloride.

EXAMPLE 312 2-Oxo-2-(5-phenoxy-1H-indol-3-yl)acetamide

Combine 2-oxo-(5-phenoxy-1H-indol-3-yl)acetyl chloride (2.15 g, 7.18mmol), and ammonium hydroxide (28-30%, 32 ml, 680 mmol) and stir for 2hours. Pour the reaction mixture into 10% (aq.) HCl, extract withdichloromethane, combine the organic layers and dry over Na₂SO₄,evaporate solvent in vacuo to give 1.94 g (96%) of title compound: ¹HNMR (300 MHz, CDCl₃) 4.87 (s, 2H), 7.51-7.91 (m, 7H), 8.13-8.24 (m, 3H).

By the method of Example 312 the following compounds were prepared: a)2-Oxo-2-(5-p-tolyloxy-1H-indol-3-yl)acetamide;

b) 2-Oxo-2-(5-o-tolyloxy-1H-indol-3-yl)acetamide; and

c) 2-Oxo-2-(5-m-tolyloxy-1H-indol-3-yl)acetamide.

EXAMPLE 314 5-Phenoxytryptamine oxalate

Add 9-oxo-2-(5-phenoxy-1H-indol-3-yl)acetamide (1.9 g, 6.86 mmol) in THF(60 mL) dropwise to a solution of LiAlH₄-THF (1.0 M, 41 mL, 41.0 mmol)in THF at room temperature. Heat the reaction mixture to reflux for 4hours and cool to room temperature. Quench the reaction mixture withwater (6 mL), followed by NaOH (2N, 3 mL). Collect the precipitate byfiltration, and wash with ether (3×50 mL). Dry the filtrate over Na₂SO₄,concentrate in vacuo, purify the residue by flash chromatography(dichloromethane/MeOH/NH₄OH) to obtain 1.0 g (59%) of free amine of thetitle compound. The oxalic salt of the title compound gives: m.p.156-157° C.; ¹H NMR (300 MHz, DMSO-d6) 2.94 (t, 2H, J=7.3 Hz), 3.00 (t,2H, J=7.3 Hz), 5.00 (br, 2H), 6.83-7.04 (m, 4H), 7.26-7.41 (m, 5H),11.05 (br, 1H); MS (ELECTROSPRAY), m/e: 341.1 (M−1); Anal. Calcd.C₁₈H₁₈N₂O₅: C, 63.15; H, 5.30; N, 8.18. Found: C, 62.97; H, 5.25; N,8.20.

By the method of Example 314 the following compounds were prepared andisolated as the oxalate, unless otherwise noted: a)5-p-Tolyloxytryptamine: ¹H NMR (300 MHz, CDCl₃) 2.31 (s, 3H), 2.83 (t,2H, J=6.4 Hz), 2.98 (t, 2H, J=6.3 Hz), 6.86-6.96 (m, 3H), 7.07-7.10 (m,3H), 7.24-7.33 (m, 2H), 8.02 (br, 1H) (isolated as the base);

b) 5-o-Tolyloxytryptamine: m.p. 187-188° C. ¹H NMR (300 MHz, DMSO-d6)2.27 (s, 3H), 2.90-3.05 (m, 4H), 6.66-6.68 (m, 1H), 6.76-6.79 (m, 1H),6.93-6.98 (m, 1H), 7.06-7.16 (m, 2H), 7.24-7.39 (m, 3H), 7.66 (br, 2H),11.05 (br, 1H); MS (ELECTROSPRAY) m/e: 265.1 (M−1-C₂H₂O₄); Anal. Calcd.C₁₉H₂₂N₂O₅: C, 64.04; H, 5.66; N, 7.86. Found: C, 63.90; H, 5.72; N,7.83; and

c) 5-m-Tolyloxytryptamine: m.p. 164-165° C.; ¹H NMR (250 MHz, DMSO-d6)2.26 (s, 3H), 2.89-3.07 (m, 4H), 4.52 (br, 2H), 6.68-6.72 (m, 2H),6.82-6.86 (m, 2H), 7.17-7.42 (m, 4H), 11.06 (br, 1H); MS (ELECTROSPRAY)m/e: 265.1 (M−1-C₂H₂O₄).

EXAMPLE 315 6-Chloro-7-fluoro-1H-indole

Combine boron trichloride (36.0 mL, 1.0 M solution in heptane, 36 mmol)and 1,2-dichloroethane (40 mL) and cool to 5° C. Add dropwise a solutionof 2-fluoro-3-chloroaniline (4.36 g, 30.0 mmol) in 20 mL1,2-dichloroethane. Warm the reaction mixture to room temperature andstir for 30 min. Add to the reaction mixture, chloroacetonitrile (2.71g, 36.0 mmol), followed by TiCl₄ (6.83 g, 3.84 mL, 36.0 mmol). Heat thereaction mixture to reflux overnight. Cool the reaction mixture to roomtemperature, add 55.0 mL of 2.5 N HCl, heat to 85° C. for 30 min. Coolto room temperature, extract with dichloromethane (3×25 mL), combine theorganic layers, wash with brine, dry over Na₂SO₄, concentrate in vacuoto give 5.1 g of 1-(2-amino-2-fluoro-3-chlorophenyl)-2-chloroethanone:¹H NMR (300 MHz, CDCl₃) 4.63 (s, 2H), 6.49 (br, 2H), 6,62-6.69 (m, 1H),7.36-7.39 (m, 1H).

Dissolve 1-(2-amino-2-fluoro-3-chlorophenyl)-2-chloroethanone in 50 mL(10% water in 1,4-dioxane, v/v) and add NaBH₄ (0.86 g, 22.8 mmol)cautiously at room temperature. Reflux the reaction mixture for about 4hour, cool to room temperature. Add 35 mL of 1N HCl and stir at roomtemperature for half an hour, extract with dichloromethane (20 mL×3),combine the organic layers and wash with H₂O and brine, dry over Na₂SO₄,and concentrate in vacuo. Chromatograph on silica gel eluting withEtOAc/hexanes to give the title compound 0.94 g (24%): ¹H NMR (300 MHz,CDCl₃) 6.55-6.58(m, 1H), 7.04-7.10 (m, 1H), 7.22-7.33 (m, 2H), 8.38 (br,1H).

By the method of Example 315 the following compounds were prepared: a)5,7-Difluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃) 6.55-6.56 (m, 1H),6.71-6.78 (m, 1H), 7.01-7.11 (m, 1H), 7.26-7.28 (m, 1H), 8.34 (br, 1H);

b) 6,7-Difluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃) 6.53-6.56 (m, 1H),6.90-6.99 (m, 1H), 7.22-7.31 (m, 2H), 8.39 (br, 1H);

c) 5,6,7-Trifluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃) 6.52-6.55 (m, 1H),7.13-7.20 (m, 1H), 7.26-7.27 (m, 1H), 8.35 (br, 1H); and

d) 4,5,7-Trifluoro-1H-indole: ¹H NMR (300 MHz, DMSO-d₆) 6.68-6.71 (m,1H), 7.20-7.29 (m, 1H), 7.57-7.59 (m, 1H), 12.07 (br, 1H); MS(electrospray) m/e: 170.0 (M−1).

e) 4,7-Difluoro-1H-indole: ¹H NMR (400 MHz, dmso-d₆): 11.91 (br s, 1H),7.44 (t, 1H, J=2.8 Hz), 6.84-6.90 (m, 1H), 6.69-6.74 (m, 1H), 6.54-6.56(m, 1H); MS (ES−): m/e 152.0 (M−1).

EXAMPLE 316 3-Formyl-6-chloro-7-fluoro-1H-indole

Add phosphorus oxychloride (0.94 g, 6.16 mmol) to DMF (12 mL, cooled inan ice bath) with vigorous stirring. After about 10 minutes, add6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in anhydrous DMF (4 mL),stir at 0° C. for 1 hour, warm to room temperature and stir overnight atroom temperature (˜16 hrs). Treat with 14.0 mL of 2N NaOH (4 eq.) withvigorous stirring. Heat the reaction to 80° C. for half an hour thencool. Pour the reaction into cold water with vigorous stirring to give asolid. Collect the solid by filtration and dry overnight in a vacuumoven at room temperature, to give the title compound: ¹H NMR (300 MHz,CD₃COCD₃/CDCl₃) 7.09 (t, 1H, J=7.7 Hz), 7.83-7.86 (m, 2H), 9.89 (s, 1H).By the method of Example 316 the following compounds were prepared: a)3-Formyl-5,7-difluoro-1H-indole: ¹H NMR (300 MHz, CD₃COCD₃) 6.98-7.06(m, 1H), 7.71-7.75 (m, 1H), 8.35 (s, 1H), 10.04 (s, 1H);

b) 3-Formyl-6,7-difluoro-1H-indole: ¹H N (300 MHz, CDCl₃) 7.10-7.19 (m,1H), 7.86-7.88 (m, 1H), 7.98-8.03 (m, 1H), 8.95 (br, 1H), 10.06 (s, 1H);

c) 3-Formyl-5,6,7-trifluoro-1H-indole: ¹H NMR (300 MHz, CD₃COCD₃)7.87-7.93 (m, 1H), 8.42 (s, 1H), 10.07 (s, 1H); and

d) 3-Formyl-4,5,7-trifluoro-1H-indole: ¹H NMR (300 MHz, DMSO-d₆)7.46-7.55 (m, 1H), 8.49 (s, 1H), 10.02 (d, 1H, J=3.7 Hz), 13.19 (br,1H).

e) 3-Formyl-4,7-difluoro-1H-indole: ¹H NMR (400 MHz, dmso-d₆): δ 13.03(br s, 1H), 10.00 (d, 1H, J=3.2 Hz), 8.36 (s, 1H), 7.07-7.13 (m, 1H),6.94-7.00 (m, 1H); MS (APCI): m/e 182.0 (M+1).

f) 3-Formyl-4,5,6,7-tetrafluoro-1H-indole: ¹H NMR (400 MHz, dmso-d₆): δ13.33 (br s, 1H), 9.94 (d, 1H, J=4.4 Hz), 8.49 (s, 1H); MS (ES−): m/e216.0 (M−1).

EXAMPLE 317 3-(2-Nitrovinyl)-6-chloro-7-fluoro-1H-indole

Combine 3-formyl-6-chloro-7-fluoro-1H-indole (1.00 g, 5.06 mmol),ammonium acetate (292 mg, 3.8 mmol, 0.75 eq.) (dry by treating withtoluene and remove the toluene in vacuo), and nitromethane (6.17 g,101.2 mmol, 20 eq.). Warm to 65° C. When the reaction is complete (byTLC), add silica gel and remove the nitromethane in vacuo. Load thesilica gel on top of short column of silica gel and elute with 25%acetone in hexanes to give, after evaporation, the title compound.

By the method of Example 317 the following compounds were prepared: a)3-(2-Nitrovinyl)-5,7-difluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃)6.68-6.81 (m, 1H), 7.16-7.21 (m, 1H), 7.60 (d, 1H, J=13.5 Hz), 7.73 (d,1H, J=2.7 Hz), 8.18 (d, 1H, J=13.5 Hz), 10.95 (br, 1H);

b) 3-(2-Nitrovinyl)-6,7-difluoro-1H-indole: ¹H NMR (300 MHz, CDCl₃)6.93-7.00 (m, 1H), 7.30-7.35 (m, 1H), 7.58 (d, 1H, J=13.5 Hz), 7.69 (d,1H, J=2.9 Hz), 8.10 (d, 1H, J=13.5 Hz), 1.18 (br, 1H): MS (electrospray)m/e: 225 (M+1), 223 (M−1);

c) 3-(2-Nitrovinyl)-5,6,7-trifluoro-1H-indole.

d) 3-(2-Nitrovinyl)-4,5,7-trifluoro-1H-indole.

e) 3-(2-Nitrovinyl)-4,7-difluoro-1H-indole: MS (ES−): m/e 223.0 (M−1).

f) 3-(2-Nitrovinyl)-4,5,6,7-tetrafluoro-1H-indole: MS(ES−): m/e 259.0(M−1).

EXAMPLE 318 6-Chloro-7-fluorotryptamine

Add dropwise 3-(2-nitrovinyl)-6-chloro-7-fluoro-1H-indole (1.20 g, 5.06mmol) in anhydrous THF to a solution of lithium aluminum hydride (30.0mL, 30.0 mmol, 1.0 M solution in THF). Heat to reflux for 2 hour andthen cool to room temperature. Quench by carefully adding 1N NaOH togive a suspension. Filter the suspension through celite and rinserepeatedly with ether. Evaporate the filtrate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting withdichloromethane, methanol, and ammonium hydroxide (10:1:01) to give,after evaporation, the title compound: ¹H NMR (300 MHz, CDCl₃) 2.87 (t,2H, J=6.6 Hz), 3.02 (t, 2H, J=6.7 Hz), 7.03-7.08 (m, 2H), 7.26-7.29 (m,1H), 8.51 (br, 1H).

By the method of Example 318 the following compounds were prepared: a)5,7-Difluorotryptamine: ¹H NMR (300 MHz, CDCl₃) 2.46 (t, 2H, J=6.5 Hz),3.01 (t, 2H, J=6.4 Hz), 6.69-6.77 (m, 1H), 7.03-7.11 (m, 2H), 8.29 (br,1H);

b) 6,7-Difluorotryptamine: ¹H NMR (300 MHz, CDCl₃) 2.87 (t, 2H, J=6.6Hz), 3.02 (t, 2H, J=6.7 Hz), 6.88-6.97 (m, 1H), 7.04 (m, 1H), 7.20-7.25(m, 1H), 8.64 (br, 1H);

c) 5,6,7-Trifluorotryptamine: ¹H NMR (300 MHz, CDCl₃) 2.83 (t, 2H, J=6.6Hz), 3.00 (t, 2H, J=6.7 Hz), 7.08-7.14 (m, 2H), 8.71 (br, 1H); MS(electrospray), m/e: 215.0 (M+1); and

d) 4,5,7-Trifluorotryptamine: ¹H NMR (300 MHz, CDCl₃) 2.93 (t, 2H, J=6.6Hz), 3.03 (t, 2H, J=6.4 Hz), 6.73-6.82 (m, 1H), 7.02 (s, 1H), 8.58 (br,1H); MS (electrospray), m/e: 215.0 (M+1), 213.0 (M−1).

f) 4,7-Difluorotryptamine: ¹HMR (400 MHz, dmso-d₆): 11.57 (br s, 1H),7.19 (s, 1H), 6.80-6.85 (m, 1H), 6.61-6.67 (m, 1H), 2.79 (s, 4H). MS(ES+): m/e 197.0 (M+1) 180.0 (M−NH₂).

g) 4,5,6,7-Tetrafluorotryptamine: ¹H NMR (400 MHz, dmso-d₆): δ 7.31 (s,1H), 2.78 (s, 4H); MS (ES+): m/e 233.0 (M+1) 216.0 (M−16).

EXAMPLE 319 N-(2-(5-Phenoxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

Combine 5-phenoxytryptamine (0.400 g, 1,59 mmol), 3-phenoxybenzaldehyde(0.377 g, 1.90 mmol) and molecular sieves 4 Å (0.40 g) in methanol (15mL) and stir for 4 h. Filter and wash the molecular sieves several timeswith MeOH. Add NaBH₄ (61.5 mg, 1.59 mmol) in portions to the filtrateand stir at room temperature for 1 h. Remove the MeOH under vacuum togive a residue, dilute the residue with dichloromethane/water, separatethe layers, extract the aqueous layer with dichloromethane, combine theorganic layers, and dry over Na₂SO₄. Concentrate in vacuo andchromatograph on silica gel eluting with dichloromethane/MeOH the titlecompound. Form the oxalate salt of the title compound: m.p. 196-198° C.;¹H NMR (300 MHz, DMSO-d6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m,18H), 11.06 (br, 1H); MS (ELECTROSPRAY) m/e: 435.3 (M+1); HRMS (ES+)calcd for C₂₉H₂₇N₂O₂ (M+H) 435.2084 found 435.2073.

By the method of Example 319 the following compounds were prepared,isolated as the oxalate except where noted:

No. Z′ R₄ Data 320 5-p-tolyloxy phenyl m.p. 204-206° C.; ¹H NMR (250MHz, DMSO-d6) 2.25 (s, 3H), 2.97-3.12 (m, 4H), 4.01 (br, 2H), 4.16 (s,2H), 6.78-6.84 (m, 3H), 7.00-7.10 (m, 10H), 7.13-7.43 (m, 4H), 11.05(br, 1H); MS (ELECTROSPRAY) m/e: 449.1 (M + 1 − C₂H₂O₄); Analysis calcd:C₃₂H₃₀N₂O₆: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.22; H, 5.59; N,5.28 321 5-o-tolyloxy phenyl m.p. 191-192° C.; ¹H NMR (300 MHz, DMSO-d6)2.28 (s, 3H), 2.99-3.15 (m, 4H), 4.17 (s, 2H), 6.63-6.66 (m, 1H), 6.756.79 (m, 1H), 6.92-7.42 (m, 15H), 9.50 (br, 2H), 11.05 (br, 1H); MS(ELECTROSPRAY) m/e: 449.1 (M + 1 − C₂H₂O₄); Anal. calcd. C₃₂H₃₀N₂O₆: C,71.36; H, 5.61; N, 5.20. Found C, 71.11; H, 5.59; N, 5.18 3225-m-tolyloxy phenyl m.p. 174-175° C. ¹H NMR (250 MHz, DMSO-d6) 2.51 (s,3H), 3.00-3.13 (m, 4H), 4.15 (s, 2H), 6.81-7.03 (m, 7H), 7.11-7.42 (m,11H), 11.05 (br, 1H): MS (ELECTROSPRAY) m/e: 449.1 (M + 1 − C₂H₂O₄) 3236-chloro-7- 2,2,2- mp 186-187° C. ¹H NMR (300 MHz, DMSO-d6) 3.13 (s,4H), 4.15 s, 2H), 4.78 (q, 2H, J=8.7 Hz), 7.07-7.12 fluoro trifluoro (m,2H), 7.21-7.24 (m, 1H), 7.37-7.45 (m, 4H), 9.44 (br, 1H), 11.72 (br,1H): ms (electrospray) m/e: 401.2 ethyl (M + 1 − HCl), 399.2 (M − 1 −HCl): Anal. calcd. C₁₉H₁₇ClF₄N₂O•HCl: C, 52.19; H, 4.15; N, 6.41. Found:C, 52.15; H, 4.14; N, 6.38 (isolated as the hydrochloride) 3246-chloro-7- 2,2,3,3- mp. 155-156° C.; 1H NMR (300 MHz, DMSO-d6) 3.13 (s,4H), 4.16 (s, 2H), 4.61 (t, 2H, J=13.5 Hz), 6.70 fluoro tetrafluoro (tt,1H, J=51.9 Hz, J=5.5 Hz), 7.08-7.10 (m, 2H), 7.11-7.12 (m, 1H),7.21-7.45 (m, 4H), 9.41 (br, 1H), 11.72 propyl (br, 1H); MS(electrospray) m/e: 433.2 (M + 1 − HCl), 431.2 (M − 1 − HCl); Anal.calcd. C₂₀H₁₈ClF₅N₂O•HCl: C, 51.19; H, 4.08; N, 5.97. Found: C, 51.27;H, 4.10; N, 6.07 (isolated as the hydrochloride) 325 5,7-difluoro 2,2,2-m.p.: 179-180° C.; ¹H NMR (300 MHz, DMSO-d6) 3.11 (s, 4H), 4.16 (s, 2H),4.77 (q, 2H, J=8.7 Hz), 6.93-6.97 trifluoro (m, 1H), 7.00-7.14 (m, 1H),7.21-7.43 (m, 5H), 9.41 (br, 1H), 11.61 (br, 1H); ms (electrospray) m/e:385.2 ethyl (M + 1 − HCl), 383.0 (M − 1 − HCl); Anal. calcd.C₁₉H₁₇F₅N₂O•HCl•0.1H₂O: C, 54.00; H, 4.34; N, 6.63. Found: C, 53.71; H,4.24; N, 6.70 (isolated as the hydrochloride) 326 5,7-difluoro 2,2,3,3-mp. 109-110° C.; ¹H NMR (300 MHz, DMSO-d6) 2.71-2.84 (m, 4H), 3.71 (s,2H), 4.53 (t, 2H, J=13.5 Hz), tetrafluoro 6.67 (tt, 1H, J=51.9 Hz, J=5.5Hz), 6.87-7.02 (m, 4H), 7.12-7.28 (m, 3H), 11.40 (br, 1H); MS(electrospray) propyl m/e: 417.0 (M + 1), 415.0 (M − 1); Anal. calcd.C₂₀H₁₈F₆N₂O•0.1H₂O: C, 57.45; H, 4.39; N, 6.70. Found: C, 57.24; H,4.08; N, 6.68 327 6,7-difluoro 2,2,2- m.p.: 164-165° C.; ¹H NMR (300MHz, DMSO-d6) 3.13 (s, 4H), 4.16 (s, 2H), 4.77 (q, 2H, J=9.1 Hz),7.00-7.13 trifluoro (m, 2H), 7.20-7.23 (m, 1H), 7.33-7.43 (m, 4H), 9.36(br, 1H), 11.57 (br, 1H); MS (electrospray) m/e: 385.2 ethyl (M + 1 −HCl), 383.3 (M − 1 − HCl); Anal. calcd. C₁₉H₁₇F₅N₂O•HCl: C, 54.23; H,4.31; N, 6.66. Found: C, 53.86; H, 4.28; N, 6.58 (isolated as thehydrochloride) 328 6,7-difluoro 2,2,3,3- m.p.: 214-215° C.; ¹H NMR (300MHz, DMSO-d6) 3.02-3.17 (m, 4H), 4.16 (s, 2H), 4.59 (t, 2H, J=13.5 Hz),tetrafluoro 6.68 (tt, 1H, J=51.9 Hz, J=5.5 Hz), 7.00-7.17 (m, 5H),7.21-7.42 (m, 4H), 11.65 (br, 1H); MS (electrospray) propyl m/e: 417.0(M + 1 − C₄H₄O₄), 415.0 (M − 1 − C₄H₄O₄); Anal. calcd.C₂₀H₁₈F₆N₂O•C₄H₄O₄•0.9H₂O: C, 52.54; H, 4.37; N, 5.11. Found: C, 52.14;H, 3.95; N, 5.49 (isolated as the maleate) 329 5,6,7-trifluoro 2,2,2-m.p.: 111-112° C.; ¹H NMR (300 MHz, DMSO-d6) 2.72-2.81 (m, 4H), 3.71 (s,2H), 4.68 (q, 2H, J=8.8 Hz), trifluoro 6.87-7.00 (m, 3H), 7.22-7.40 (m,3H), 11.58 (br, 1H); MS (electrospray) m/e: 403.1 (M + 1), 401.2 (M −1). ethyl Anal. calcd. C₁₉H₁₆F₆N₂O: C, 56.72; H, 4.01; N, 6.96. Found:C, 56.61; H, 3.92; N, 6.96 (isolated as the base) 330 5,6,7-trifluoro2,2,3,3- m.p.: 223-224° C.; ¹H NMR (300 MHz, DMSO-d6) 3.11 (s, 4H), 4.15(s, 2H), 4.61 (t, 2H, J=13.5 Hz), 6.70 (tt, tetrafluoro 1H, J=51.9 Hz,J=5.5 Hz), 7.08-7.12 (m, 1H), 7.19-7.25 (m, 1H), 7.36-7.43 (m, 3H),7.52-7.58 (m, 1H), 9.50 propyl (br, 1H), 11.78 (br, 1H); MS(electrospray) m/e: 435.1 (M + 1 − HCl), 433.1 (M − 1 − HCl); Anal.calcd. C₂₀H₁₈F₆N₂O•HCl•0.1H₂O: C, 50.83; H, 3.88; N, 5.93. Found: C,50.60; H, 3.74; N, 6.07 (isolated as the hydrochloride) 3314,5,7-trifluoro 2,2,2- m.p.: 243-244° C.; ¹H NMR (300 MHz, DMSO-d6)3.16-3.21 (m, 4H), 4.18 (s, 2H), 4.75 (q, 2H, J=8.8 Hz), trifluoro7.11-7.25 (m, 3H, 7.39-7.45 (m, 3H), 9.37 (br, 1H), 11.90 (br, 1H); MS(electrospray) m/e: 403.1 (M + 1 − HCl), ethyl 401.0 (M − 1 − HCl);Anal. calcd. C₁₉H₁₆F₆N₂O•HCl: C, 52.00; H, 3.91; N, 6.38. Found: C,51.83; H, 3.62; N, 6.55 (isolated as the hydrochloride 3324,5,7-trifluoro 2,2,3,3- m.p.: 261-262° C.; ¹H NMR (300 MHz, DMSO-d6)3.18 (s, 4H), 4.17 (s, 2H), 4.61 (t, 2H, J=13.5 Hz), 6.69 (tt,tetrafluoro 1H, J=51.9 Hz, J=5.5 Hz), 7.09-7.13 (m, 1H), 7.17-7.26 (m,2H), 7.32-7.42 (m, 3H), 9.37 (br, 1H), 11.92 (br, 1H); propyl MS(electrospray) m/e: 435.1 (M + 1 − HCl), 433.1 (M − 1 − HCl); Anal.calcd. C₂₀H₁₇F₇N₂O•HCl, C, 51.02; H, 3.85; N, 5.95. Found: C, 50.62; H,3.79; N, 6.00 (isolated as the hydrochloride) 333 7-cyano 2,2,2- mp.241-242° C.; ¹H NMR (300 MHz, DMSO-d6) 3.15 (s, 4H), 4.17 (s, 2H), 4.78(q, 2H, J=8.7 Hz), 7.10-7.22 trifluoro (m, 3H), 7.33-7.43 (m, 3H),7.60-7.62 (m, 1H), 7.95-7.97 (m, 1H), 9.29 (br, 2H), 11.90 (br, 1H); MSethyl (electrospray) m/e: 374.2 (M + 1 − HCl), 372.0 (M − 1 − HCl);Anal. calcd. C₂₀H₁₈F₃N₃O•HCl•0.2 H₂O: C, 58.10; H, 4.73; N, 10.16.Found: C, 57.91; H, 4.56; N, 10.08. 334 7-cyano 2,2,3,3- mp. 212-213°C.; ¹H NMR (300 MHz, DMSO-d6) 3.16 (s, 4H), 4.16 (s, 2H), 4.61 (t, 2H,J=13.6 Hz), 6.69 (tt, tetrafluoro 1H, J=51.9 Hz, J=5.5 Hz), 7.09-7.22(m, 3H), 7.33-7.43 (m, 3H), 7.60-7.63 (m, 1H), 7.96-7.98 (m, 1H), 9.34(br, ethyl 2H), 11.92 (br, 1H); MS (electrospray) m/e: 406.2 (M + 1 −HCl), 404.0 (M − 1 − HCl); Anal. calcd. C₂₁H₁₉F₄N₃O•HCl, C, 57.08; H,4.56; N, 9.51. Found: C, 57.12; H, 4.61; N, 9.53.

EXAMPLE 335 2-Fluoro-3-phenoxybenzaldehyde

Cool a solution of 2,2,6,6-tetramethylpiperidine (5.1 mL, 30.0 mmol) inTHF (40 mL) to −75° C. Add dropwise n-Butyllithium (18.7 mL, 30.0 mmol,1.6M in hexanes) and stir for 10 min at −78° C. Add dropwise2-fluorophenyl phenyl ether (4.7 g, 25.0 mmol), stir 2 h at −78° C. AddN,N-dimethylformamide (2.3 mL, 30.0 mmol) dropwise over 15 min. Stir theresulting mixture for 3 h at −78° C. and allow to warm to ambienttemperature over 16 h. Quench the reaction mixture with water (50 mL),extract with ethyl acetate, dry over Na₂SO₄, filter and concentrateunder reduced pressure to give an oil. Crystallize the oil with hexanesto give a solid, collect and recrystallize from hexanes/ethylacetate/methylene chloride to give the title compound: mp 75-77° C.;MS(m/e): 216 (M⁺); Calculated for C₁₃H₉FO₂: Calcd: C, 72.22; H, 4.20.Found: C, 72.41; H, 4.23. Purification of the mother liquors by silicagel chromatography (2-3% ethyl acetate/hexanes) gives an additionalamount of the title compound: MS(m/e): 216 (M⁺).

By the method of Example 335 the following compound was prepared: a)6-Fluoro-3-phenoxybenzaldehyde: MS(m/e): 216 (M⁺).

EXAMPLE 336 3-Ethoxybenzaldehyde

Combine 3-hydroxybenzaldehyde (5.6 g, 46 mmol) and 1-iodoethane (10.7 g,69 mmol) in DMSO (25 mL) and warm to 80° C. Treat with of cesiumcarbonate (22.4 g, 69 mmol) in portions. During the addition thetemperature begin to rise so the bath is removed. Stir the reaction at80° C. for 1 hour, pour into 200 mL brine and extract twice with 150 n-Ldiethyl ether. Wash the combine extracts twice with 200 mL brine, dryover MgSO₄ and concentrate under vacuum to give an oil. Purification bychromatography (SiO₂; 2.5% EtOAc in hexanes) affords 5.73 g (38 mmol;83%) of the title compound as an oil: ¹H NMR (CDCl₃) 9.94 (s, 1H),7.42-7.41 (m, 2H), 7.36-7.35 (m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q,2H), 1.64-1.40 (t, 3H).

By the method of Example 336 the following compounds were prepared: a)3-Propoxybenzaldehyde: ¹H NMR (CDCl₃) 9.95 (s, 1H), 7.43-7.41 (m, 2H),7.37-7.36 (m, 1H), 7.17-7.14 (m, 1H), 9.98-3.95 (t, 2H), 1.84-1.79 (m,2H), 1.05-1.02 (t, 3H).

EXAMPLE 337 p-Toluene-3-(2,2,3,3-tetrafluoropropoxy)tosylate

Add pyridine (1.9 L) (dried over molecular sieves 4 Å) to around-bottomed flask (5 L), under inert atmosphere and equipped with amechanical agitator and add 2,2,3,3-tetrafluoro-1-propanol (604.5 g,4.58 mol). Cool the mixture to 0° C. with an ice-bath. Addp-toluenesulfonyl chloride (960 g, 5.04 mol) over 20 min in 4 portionsto the reaction mixture and stir. After 20 min., cooling on anice-bath), a precipitate is formed. Stir the reaction mixture for 1 h at0° C. and 2 h at 20° C. Pour the reaction mixture, with agitation, overan ice-water mixture (1.44 L) and leave overnight (18 h) at 2° C. Thecrude tosylate derivative separates from the aqueous mixture as an oilymaterial (1.34 kg) containing 14% w/w pyridine which corresponds to 1.15kg of the tosylate (87.8%). The crude material is carried to the nextreaction step without further purification: ¹H-RMN is consistent.

EXAMPLE 338 3-(2,2,3,3,3-Pentafluoropropoxy)benzaldehyde

Combine 3-hydroxybenzaldehyde (137.6 g, 1.127 mol),p-toluene-3-(2,2,3,3,3-pentafluoropropoxy)tosylate (243 g, 0.799 mol),potassium carbonate (220 g, 1.597 mol) and dimethylformamide (2451 mL)in a double-wall 4 L reactor equipped with a reflux condenser and amechanical agitator, and heat at 110° C. for 46.5 h under argonatmosphere. Cool the reaction mixture to room temperature and filterthrough a bed of 400 g of silica gel. Elute silica gel bed with 2.451 mLof ethyl acetate. Pour the combined organic layers over 7.3 L ofice-water. Add 10 N sodium hydroxide (500 mL) to this mixture and stirfor 1 h. Separate the aqueous phase and extract with ethyl acetate (1000mL). Pool the organic phase, wash with water (1000 mL) and brine (750mL). Evaporation of the organic solvents under reduced pressure provides159.79 g of a brown oily material containing the crude title compound.Purification by fractional distillation (two successive cycles) underreduced pressure (2 mm Hg) using a distillation apparatus equipped witha 30 cm length adiabatic column to gives a fraction of 52.4 g of theexpected product (96.2% area by HPLC).

EXAMPLE 339 3-(3,3,3-Trifluoropropoxy)benzaldehyde

Combine 3-hydroxybenzaldehyde (130.2 g, 1.066 mol),3,3,3-trifluoropropoxy tosylate (143 g, 0.533 mol), potassium carbonate(147.35 g, 1,066 mol) and absolute ethanol (1430 mL) in a three-neckedround-bottomed flask equipped with a reflux condenser and a magneticstirred and reflux for 4 h under argon atmosphere. Concentrate thereaction mixture under reduced pressure. Pour the concentrated mixtureover 1N sodium hydroxide (2145 mL), stir for 30 min and extract withdichloromethane (2145 mL). Decant the organic layer wash with 1N sodiumhydroxide (2145 mL). After separation, wash the organic layersuccessively twice by 1 L water (pH aqueous phase 7), dry over 30 gmagnesium sulfate, evaporate the dichloromethane organic layer todryness under reduced pressure to yield 55.4 g of the title compound(0.254 mol, 47.6% yield) as a slightly yellow oily material.

EXAMPLE 340N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-2-fluoro-3-phenoxy-benzylamine

Combine 6-fluorotryptamine (419 mg, 2.35 mmol) and2-fluoro-3-phenoxybenzaldehyde (610 mg, 2.82 mmol) in absolute ethanol(6 mL). Heat the mixture to 65° C. to give a homogeneous solution. Add 3Å molecular sieves (400 mg) to the mixture and heat to refluxtemperatures for 5 h. Cool the reaction mixture to ambient temperatureand add sodium borohydride (267 mg, 7.1 mmol). Stir the mixture for 18 hat ambient temperature. Cool the reaction mixture on a water bath,quench with acetone, dilute with ethanol and acetone, and filter themolecular sieves. Concentrate the filtrate under reduced pressure,dilute with 1N NaOH, extract with ethyl acetate, wash with brine, dry(Na₂SO₄), filter and concentrate under reduced pressure to give 1.0 g ofan oil. Chromatograph on silica gel eluting with 1%, 4% 2N ammonia inmethanol/methylene chloride gives a clear colorless oil. Formation ofthe hydrochloride salt in ethyl acetate/methanol gives the hydrochlorideof the title compound: mp 173-174.5° C.; MS(m/e): 379 (M+1), 377 (M−1);Calculated for C₂₃H₂₀F₂N₂O.HCl: Calcd: C, 66.59; H, 5.10; N, 6.75.Found: C, 66.50; H, 5.09; N, 6.73.

EXAMPLE 341N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-6-fluoro-3-phenoxy-benzylamine

The method of Example 340 gives the hydrochloride of the title compound:mp 183.5-185.5° C.; MS(m/e): 379 (M+1), 377 (M−1); Calculated forC₂₃H₂₀F₂N₂O.HCl: Calcd: C, 66.59; H, 5.10; N, 6.75. Found: C, 66.54; H,5.11; N, 6.68.

By the method of Example 340 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 342 5-methoxy ethyl ISMS 325 (M + 1); Analysis forC₂₀H₂₅C₁N₂O₂ 0.2EtOH 0.1H₂O: calcd: C, 65.88; H, 7.16; N, 9.53; found:C, 65.90; H, 6.97; N, 7.16; ¹H NMR (DMSO-d6) 10.85 (s, 1H), 9.43 (bs,2H), 7.42-7.22 (m, 4H), 7.18-7.10 (m, 2H), 7.05-7.0 (m, 1H), 6.32-6.15(m, 1H), 4.3-4.15 (m, 2H), 4.15-4.05 (q, 2H), 3.85 (s, 3H), 3.15 (s,4H), 1.45-1.35 (t, 3H) 343 5-methoxy propyl ISMS 339 (M + 1); Analysisfor C₂₁H₂₇ClN₂O₂: calcd: C, 67.28; H, 7.23; N, 7.47; found: C, 67.28; H,7.30; N, 7.13; ¹H NMR (DMSO-d6) 10.85 (s, 1H), 9.43 (bs, 2H), 7.35-7.15(m, 4H), 7.1-7.05 (m, 2H), 7.0-6.92 (m, 1H), 6.7-6.6 (m, 1H), 4.3-4.16(m, 1H), 4.15-4.05 (q, 2H), 3.85 (s, 3H), 3.15 (s, 4H), 1.45-1.35 (t,3H) 344 5-fluoro 2,2,2- ISMS 367 (M + 1); Analysis for C₁₉H₁₉ClF₄N₂O:calcd: C, 56.65; H, 4.75; N, 6.95; found: C, 56.37; H, 4.83; N,trifluoro 6.81 (base) ethyl 345 5-methoxy 2,2,2- Analysis forC₂₀H₂₂ClF₃N₂O₂: calcd: C, 57.91; H, 5.34; N, 6.75; found: C, 57.72; H,5.17; N, 6.61; ISMS 379 trifluoro (M + 1) ethyl 346 5-fluoro 2,2,3,3,3-ISMS 417 (M + 1); Analysis for C₂₀H₁₈F₆N₂O C₂H₂O₄: calcd: C, 51.18; H,3.98; N, 5.53; found: C, 51.18; H, pentafluoro 3.91; N, 5.51 (isolatedas the oxalate) propyl 347 5-methoxy 2,2,3,3,3- ISMS 429 (M + 1);Analysis for C₂₁H₂₁F₅N₂O ₂ 1.2C₂H₂O₄ 0.8H₂O: calcd: C, 51.02; H, 4.57;N, 5.09; found: pentafluoro C, 50.64; H, 4.23; N, 5.15 (isolated as theoxalate) propyl 348 5-methoxy 2,2,3,3- ISMS 411 (M + 1) Analysis forC₂₁H₂₂F₄N₂O₂ C₂H₂O₄ 0.1H₂O: C, 55.0; H, 4.86; N, 5.58; found: C, 54.74;tetrafluoro calcd: H, 4.74; N, 5.58 (isolated as the oxalate) propyl 3495-methoxy 3,3,3- Analysis for C₂₁H₂₃F₃N₂O₂ HCl: calcd: C, 58.81; H,5.64; N, 6.53; found: C, 58.42; H, 5.44; N, 6.51; ISMS 393 trifluoro(M + 1) propyl 350 5-fluoro 2,2,3,3- Analysis for C₂₀H₂₀F₄N₂O HCl:calcd: C, 57.63; H, 5.08; N, 6.72; found: C, 57.49; H, 5.04; N, 6.76;ISMS 381 tetrafluoro (M + 1) propyl 351 4-chloro-5- 2,2,2- Analysis forC₂₀H₂₀ClF₃N₂O₂ HCl: calcd: C, 53.47; H, 4.71; N, 6.24; found: C, 53.33;H, 4.65; N, 6.21; ISMS methoxy trifluoro 413 (M + 1) ethyl 3524-chloro-5- 2,2,3,3- Analysis for C₂₁H₂₁ClF₄N₂O₂ HCl: calcd: C, 52.40;H, 4.61; N, 5.82; found: C, 52.25; H, 4.50; N, 5.80; ISMS methoxytetrafluoro 445 (M + 1) propyl 353 4-chloro-5- 3,3,3- Analysis forC₂₁H₂₂ClF₃N₂O₂ HCl: calcd: C, 54.4; H, 5.00; N, 6.05; found: C, 54.18;H, 4.86; N, 6.06; ISMS 427 methoxy trifluoro (M + 1) propyl

By the method of Example 340 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 360 3-chloro 2,2,2-trifluoro ISMS 344 (M + 1); Analysisfor ethyl C₁₇H₁₈ClF₃NO calcd: C, 53.70; H, 4.77; N, 3.68; found: C,53.61; H, 4.96; N, 3.66 361 3-trifluoro 2,2,2-trifluoro ISMS 378 (M +1); Analysis for C₂₀H₁₉F₆NO5: methyl ethyl calcd: C, 51.40; H, 4.10; N,3.0; found: C, 51.26; H, 4.06; N, 3.07 (isolated as the oxalate) 3623-chloro 2,2,3,3,3- ISMS 394 (M + 1); Analysis for pentafluoroC₁₈H₁₈C₁₂F₅NO: calcd: C, 50.25; H, 4.22; N, propyl 3.26; found: C,50.38; H, 4.03; N, 3.45 363 3-trifluoro 2,2,3,3,3- ISMS 428 (M + 1);Analysis for C₁₉H₁₇F₈NO methyl pentafluoro C₂H₂O₄: calcd: C, 48.75; H,3.70; N, 2.70; propyl found: C, 48.76; H, 3.67; N, 2.79 (isolated as theoxalate) 364 3-chloro 2,2,3,3- Analysis for C₁₈H₁₈ClF₄NO C₂H₂O₄:tetrafluoro calcd: C, 51.57; H, 4.33; N, 3.01; propyl found: C, 51.92;H, 4.29; N, 3.08; ISMS 376 (M + 1) 365 3-trifluoro 2,2,3,3- Analysis forC₁₉H₁₈F₇NO C₂H₂O₄: calcd: C, methyl tetrafluoro 50.51; H, 4.04; N, 2.81;found: C, 50.48; H, propyl 4.02; N, 2.85; ISMS 410 (M + 1) (isolated asthe oxalate) 366 3-trifluoro 3,3,3-trifluoro Analysis for C₁₉H₁₉F₆NOHCl: calcd: methyl propyl C, 53.34; H, 4.71; N, 3.27; found: C, 53.23;H, 4.73; N, 3.28; ISMS 392 (M + 1) 367 3-chloro 3,3,3-trifluoro Analysisfor C₁₈H₁₉ClF₃NO HCl: calcd: C, propyl 54.84; H, 5.11; N, 3.55; found:C, 54.74; H, 5.02; N, 3.11; ISMS 358 (M + 1)

EXAMPLE 370N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

Combine 6-fluorotryptamine oxalate (350 mg, 1.3 mmol),N,N-diisopropylethylamine (506 mg, 3.9 mmol),3-(2,2,2-trifluoroethoxy)benzaldehyde (266 mg, 1.3 mmol), and 4 Åmolecular sieves (4 g) in EtOH (30 mL) and reflux for 7 hours. Decantthe liquid into a separate flask and treat with NaBH₄ (148 mg, 3.9mmol). Stir 1 hour, concentrate the mixture in vacuo to give a residue.Partition the residue between 25 mL 5 N NaOH and 25 mL dichloromethane.Extract the aqueous layer with 25 mL dichloromethane, combine theorganic layers, dry over MgSO₄, and concentrate to approximately a 20 mLvolume. Chromatograph on silica gel eluting with 1% MeOH in CHCl₃ mixedwith conc. NH₄OH to give the title compound. Combine an EtOAc solutionof the title compound with an EtOAc solution of one equivalent of oxalicacid to give a solid, filter, and dry under vacuum to give the oxalatesalt of the title compound: ISMS 367 (M+1); Analysis for C₉H₁₉CIF₄N₂O:calcd: C, 55.27; H, 4.42; N, 6.14; found: C, 55.17; H, 4.38; N, 6.09.

By the method of Example 370 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 372 5-fluoro 2,2,3,3- ISMS 399 (M + ); Analysis forC₁₉H₁₇F₈NO tetrafluoro C₂H₂O₄ H₂O: calcd: C, 53.51; H, 4.41; N, propyl5.67; found: C, 53.12; H, 4.21; N, 5.63 (isolated as the oxalate) 3736-fluoro 2,2,3,3,3- Analysis for C₂₀H₁₈F₆N₂O HCl: calcd: C, pentafluoro53.05; H, 4.23; N, 6.19; found: C, 52.88; H, propyl 4.05; N, 6.12; ISMS417 (M + 1) 374 6-chloro-5- 2,2,2-trifluoro Analysis for C₂₀H₂₀ClF₃N₂O₂HCl: calcd: C, methoxy ethyl 53.47; H, 4.71; N, 6.24; found: C, 53.65;H, 4.85; N, 6.45; ISMS 413 (M + 1) (Form the salt in 50 mL 50/50THF/EtOH using polyvinyl pyridine hydrochloride) 375 6-chloro-5-2,2,3,3- Analysis for C₂₁H₂₁ClF₄N₂O₂ HCl: calcd: C, methoxy tetrafluoro52.40; H, 4.61; N, 5.82; found: C, 52.15; H, propyl 4.51; N, 5.69; ISMS445 (M + 1) 376 6-fluoro 2,2,3,3- Analysis for C₂₀H₁₉F₅N₂₀HCl: calcd: C,tetrafluoro 55.24; H, 4.64; N, 6.44; found: C, 55.06; H, propyl 4.63; N,6.44; ISMS 399 (M + 1) 377 6-fluoro 3,3,3-trifluoro Analysis forC₂₀H₂₀F₄N₂O HCl: calcd: C, propyl 54.83; H, 5.11; N, 3.55; found: C,54.74; H, 5.02; N, 3.11; ISMS 381 (M + 1) 378 5-trifluoro 2,2,3,3,3-Analysis for C₂₁H₁₈F₈N₂O_(2 HCl: calcd: C,) methoxy pentafluoro 48.62;H, 3.69; N, 5.40; found: C, 48.55; H, propyl 3.48; N, 5.33; ISMS 483(M + 1) 379 5-trifluoro 2,2,3,3- Analysis for C₂₁H₁₉F₇N₂O₂ HCl: calcd:C, methoxy tetrafluoro 50.36; H, 4.02; N, 5.59; found: C, 50.27; H,propyl 3.92; N, 5.63; ISMS 465 (M + 1) 380 5-trifluoro 2,2,2-trifluoroAnalysis for C₂₀H₁₈F₆N₂O₂ HCl: calcd: C, methoxy ethyl 51.24; H, 4.08;N, 5.98; found: C, 51.33; H, 4.09; N, 6.26; ISMS 433 (M + 1)

EXAMPLE 381 N-t-Butoxycarbonyl-2-(5-in-tolyloxy-1H-indol-3-yl)ethylamine

The method of Example 20 gives the title compound: ¹H NMR (300 MHz,CDCl₃) 1.41 (s, 9H), 2.30 (s, 3H), 2.89 (t, 2H, J=6.7 Hz), 3.41(m, 2H),6.74-6.85 (m, 3H), 6.93-6.99 (m, 1H), 7.07-7.35 (m, 4H), 8.05 (br, 1H).

EXAMPLE 382 N-Methyl-2-(5-m-tolyl)tryptamine

The method of Example 21 gives the title compound and formation of theoxalate salt gave: m.p. 182-183° C.; ¹H NMR (250 MHz, DMSO-d6) 2.26 (s,3H), 2.59 (s, 3H), 2.98-3.18 (m, 4H), 6.68-6.72 (m, 2H), 6.82-6.86 (m,2H), 7.17-7.22 (m, 1H), 7.29-7.42 (m, 3H), 11.06 (br, 1H); MS(ELECTROSPRAY) m/e: 281.2 (M+1-C₂H₂O₄); Anal. calcd. C₂₀H₂₂N₂O₅: C,64.85; H, 5.99; N, 7.56. Found: C, 65.01; H, 5.74; N, 7.71.

EXAMPLE 383N-Methyl-N-(2-(5-m-tolyloxy-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

The method of Example 301 gives the title compound and formation of theoxalate salt gave: m.p. 142-144° C.; ¹H NMR (250 MHz, DMSO-d6) 2.24 (s,3H), 2.634 (s, 3H), 3.01-3.12 (m, 4H), 3.92 (br, 2H)), 4.16 (s, 2H),6.65-6.70 (m, 2H), 6.81-6.84 (m, 2H), 6.99-7.03 (m, 3H), 7.12-7.26 (m,6H), 7.34-7.43 (m, 4H), 11.00 (br, 1H); MS (ELECTROSPRAY) m/e: 463.4(M+1+C₂H₂O₄); Anal. calcd. C₃₃H₃₂N₂O₆: C, 71.72; H, 5.84; N, 5.07.Found: C, 71.44; H, 5.89; N, 4.99.

EXAMPLE 384 5-Nitrotryptamine

Warm mixture of 5-nitroindole (10 g, 62 mmol) and 200 mL glacial aceticacid to 70° C. and treat with Eschenmoser's salt (12 g, 65 mmol).Concentrate after 1 hour the reaction under vacuum to dryness. Mix theresidue with 200 mL toluene, reconcentrate to dryness then partitionbetween 200 mL concentrated ammonium hydroxide and 200 mL EtOAc. Whenall solids dissolved, Separate the layers and extract the aqueous layer200 mL EtOAc. Dry the combined organic layer over MgSO₄ and concentrateto give N,N-dimethyl-5-nitrotryptamine as a solid. Dissolve theN,N-dimethyl-5-nitrotryptamine obtained above in 200 mL dry DMSO, treatwith iodomethane (7.7 mL, 17.5 g, 124 mmol), and stir for 1 hour atambient temperature. Add KCN (40 g, 621 mmol) and 18-crown-6 (0.5 g).Warm the reaction to 110° C. for 45 minutes, cool, poured onto ice thensaturate with NaCl. Extract the quenched reaction mixture with EtOAc,combine the extracts, and wash 3 times with brine. Dry over MgSO₄ andconcentrate under vacuum. chromatograph on silica gel eluting with 1%MeOH in CHCl₃ to give (5-nitro-1H-indol-3-yl)acetonitrile as a solid:FDMS 201 (M+); Analysis for C₁₀H₇N₃O₂: calcd: C, 59.70; H, 3.51; N,20.89; found: C, 59.32; H, 3.52; N, 20.56.

Dissolve (5-nitro-1H-indol-3-yl)-acetonitrile (9 g, 44.7 mmol) in 250 mLdry THF and treat with 90 mL 1 M B₃ in THF at ambient temperature. Stirovernight and quench the reaction cautiously by the dropwise addition of10 mL water. Concentrate to dryness under vacuum and partition theresidue between 5 N HCl and EtOAc. Extract the aqueous layer with EtOAcand combine with the original EtOAc layer. Treat the aqueous layer with5 N NaOH and extract 3 times with 10% MeOH in EtOAc. Purify by flushingthe extracts through a pad of 100 g SCX ion exchange resin, rinsing with2 liters of MeOH which was discarded, and then eluting with the 2 M N3in MeOH and concentrating to give the title compound as a dark solid:ISMS 206 (M+1); Analysis for C₂₀H₁₈F₆N₂O₂ 0.3H₂O 0.1C₇H₈: calcd: C,57.34; H, 5.74; N, 19.29; found: C, 57.30; H, 5.38; N, 19.08; ¹H NMR(DMSO-d6) 11.9-11.2 (bs, 1H), 8.50-8.49 (d, 1H), 7.95-7.92 (m, 1H),7.47-7.45 (m, 1H), 7.38 (s, 1H), 2.79 (s, 4H), 2.2-1.3 (bs, 2H).

EXAMPLE 385 6-Nitrotryptamine

The method of Example 384 gives (6-nitro-1H-indol-3-yl)-acetonitrile:ISMS 200 (M−1); Analysis for C₁₀H₇N₃O₂ 0.1H₂O: calcd: C, 59.17; H, 3.58;N, 20.70; found: C, 59.04; H, 3.28; N, 20.39 which gives the titlecompound: ISMS 206 (M+1); ¹H NMR (DMSO-d6) 11.5 (bs, 2H), 8.26 (s, 1H),7.84-7.81 (m, 1H), 7.68-7.66 (m, 1H), 7.57 (s, 1H), 2.80-74 (m, 4H)(indole N—H not observable).

EXAMPLE 390 N-(2-(5-Nitro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

The method of Example 340 gives the title compound, salt formation in 10mL EtOH with 0.25 mL 5 N HCl and 40 mL toluene then concentrating to asolid give the hydrochloride of the title compound: Analysis forC₂₃H₂₁N₃O₃ HCl 0.2 EtOH: calcd: C, 64.62; H, 5.17; N, 9.75; found: C,64.89; H, 5.40; N, 9.75; ISMS 388 (M+1).

By the method of Example 390 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 391 5-nitro 2,2,2-trifluoro ISMS 444 (M + 1); Analysisfor ethyl C₂₀H₂₀ClF₄N₃O₃•0.1 H2O: calcd: C, 52.87; H, 4.48; N, 9.74;found: C, 52.63; H, 4.34, N, 9.67 392 5-nitro 2,2,3,3- ISMS 444 (M + 1);Analysis for tetrafluoro C₂₀H₂₀ClF₄N₃O₃: calcd: C, 52.01; H, 4.36; N,propyl 9.10; found: C, 51.94; H, 4.19; N, 8.93 393 6-nitro2,2,2-trifluoro ISMS 394 (M + 1); ¹H NMR (CDCl₃-freebase) ethyl 8.47(bs, 1H), 8.31-8.30 (m, 1H), 8.01-7.98 (m, 1H), 7.63-7.61 (m, 1H),7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 6.94-6.92 (m, 1H), 6.88 (s, 1H),6.80-6.77 (m, 1H), 4.33-4.26 (m, 2H), 3.79 (s, 2H), 3.00-2.93 (m, 4H),1.54 (s, 1H) 394 6-nitro 2,2,3,3- ISMS 426 (M + 1); Analysis forC₂₀H₁₉F₄N₃O₃: tetrafluoro calcd: C, 52.01; H, 4.36; N, 9.10; found: C,propyl 51.96; H, 4.16; N, 8.76 395 6-nitro 2,2,3,3,3- ISMS 444 (M + 1);Analysis for C₂₀H₁₈F₅N₃O₃: pentafluoro calcd: C, 50.06; H, 3.99; N,8.76; found: C, propyl 49.76; H, 3.86; N, 8.67

EXAMPLE 396 5-Amino-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

Combine N-(2-(5-nitro-1H-indol-3-yl)ethyl)-3-phenoxybenzylaminehydrochloride (250 mg, 0.64 mmol) and NiCl₂-6H₂O (460 mg, 1.9 mmol) in30 mL MeOH and treat with NaBH₄ (73 mg, 1.9 mmol). After 1 hourconcentrate to dryness, partition between EtOAc and concentrated NH₄OH.Extract the aqueous layer with EtOAc, combine the organic layer, dryover MgSO₄ and concentrate to dryness. Chromatograph on silica geleluting with a stepwise gradient 20/75/5 THF/hexanes/Et₃N then 40/55/5THF/hexanes/Et₃N gives the title compound as an oil. Additionalchromatograph on silica gel eluting with 1% MeOH in CHCl₃ mixed withconc. NH₄OH gives the title compound as an oil. Treatment with in 10 mLEtOH with 0.25 mL 5 N HCl and 40 mL toluene then concentrating give thetitle compound as the hydrochloride: Analysis for C₂₃H₂₃N₃O 2.6 HCl 0.6EtOH: calcd: C, 59.66; H, 5.83; N, 9.07; found: C, 59.30; H, 5.48; N,8.82; ISMS 358 (M+1).

By the method of Example 396 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 397 5-amino 2,2,2-trifluoro Analysis for C₁₉H₂₀F₃N₃O 2HCl0.2 CHCl₃ 0.3 ethyl CH₃OH: calcd: C, 49.85; H, 5.02; N, 8.94; found: C,50.05; H, 4.99; N, 8.73; ISMS 364 (M + 1) 398 5-amino 2,2,3,3- ¹H NMR(DMSO-d6) 11.3 (bs, 1H), 10.25 (bs, tetrafluoro 3H), 9.6 (bs, 2H), 7.6(s, 1H), 7.5-7.35 (m, 4H), propyl 7.3-7.2 (m, 1H), 7.2-7.0 (m, 2H),6.9-6.5 (d, 1H), 4.65-4.5 (t, 2H), 4.25 (s, 2H), 3.3 (s, 4H); Analysisfor C₂₀H₂₁F₄N₃O 2HCl: calcd: C, 51.29; H, 4.95; N, 8.97; found: C,51.26; H, 4.98; N, 8.26 399 6-amino 2,2,2-trifluoro ISMS 363 (M+);C₁₉H₂₂C₁₂F₃N₃O•0.4 H2O: ethyl calcd: C, 51.45; H, 5.18; N, 9.48; found:C, 51.45; H, 5.10; N, 9.63 400 6-amino 2,2,3,3- ISMS 393 (M+);C₂₀H₂₃C₁₂F₄N₃O•0.2 H2O: tetrafluoro calcd: C, 50.90; H, 5.00; N, 8.90;found: C, propyl 50.73; H, 4.82; N, 8.65

EXAMPLE 401 6-Fluorotryptamine

Combine 6-fluoroindole (108 g, 0.8 mol) and dichloromethane (324 ml).Cool in an ice bath. Add trifluoroacetic acid (308 ml) over a fewminutes (exothermic). Add a solution ofZ-1-dimethylamino-2-nitroethylene (94.7 g, 0.816 mol) in dichloromethane(600 ml) during 40 minutes while maintaining the temperature at about0-5° C. After 45 minutes, warm to about 20° C. After 2 hours, pour over1.2 L ice water and stirring overnight with seeding to give a solid.Collect the solid by filtration, wash first with 100 ml of a mixturedichloromethane-cyclohexane 1/1, then with 750 ml of water and dry at40° C. to give 3-(2-nitrovinyl)-6-fluoroindole.

Combine LiAlH₄ (48.8 g, 1.286 moles, 5 equiv.) and THF (848 ml) and coolin an ice-water bath to about 6° C. while keeping the temperature below32° C. Add a solution of 3-(2-nitrovinyl)-6-fluoroindole (53 g, 0.257mol, 1 equiv.) in THF (694 ml) while keeping the temperature below about31° C. Allow to stir at ambient temperature. After 2.5 hours, quenchwith a mixture of 49 ml of water and 49 ml of THF, then with 49 ml ofNaOH 15% and finally with 49 ml of water. Keep the temperature below−32° C. during the quench. Stir for 1.5 hours, filter through a celitebed and wash with THF. Evaporate to residue, dissolve in 750 ml ofdiethyl ether and cool in an ice-water bath. Add a solution ofHCl/diethyl ether to give a solid. Stir for 1 hour, collect the solid byfiltration, wash with diethyl ether, and dry under reduced pressure at45° C. to give the hydrochloride of the title compound.

EXAMPLE 402N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine

Combine 6-fluorotryptamine hydrochloride (90 g, 0.419 mol) and water(900 ml). Add an aqueous solution of NaOH (2N, 230 ml) anddichloromethane (900 ml). After 1 hour, separate the organic layer,extract the aqueous layer with dichloromethane, combine the organiclayers, wash water, dry over MgSO₄, and evaporate to a residue. Combinethe residue and toluene (200 ml) and evaporate to give 78.45 g of abrown oil. Combine the above 78.45 g with another 41.4 g batch toprovide 6-fluorotryptamine. Combine 6-fluorotryptamine (119.85) andethanol (3.325 L), add 2,2,3,3-tetrafluoropropylbenzaldehyde (176 g,0.745 moles, 1.2 equiv.) and 150 g of molecular sieve 3 Å. Heat toreflux. After 2 hours, cool to RT room temperature and add NaBH₄ (35.2g, 0.93 mol, 1.5 equiv.). After 1 hour, filter through celite and washwith 500 ml of ethanol. Evaporate the filtrate under reduced pressure togive an oily residue. Partition the residue between water anddichloromethane. Separate the layers, extract the aqueous later withdichloromethane, combine organic layers, wash with brine and dry overMgSO₄. Filter and evaporate under reduced pressure to give the titlecompound.

The HCl salt is formed as follows: CombineN-(2-(6-fluror-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylamine(387 g, 0.97 moles) and diethyl ether (3.95 L) of at room temperature.Add dropwise a solution of HCl/Et₂O (298 ml) over 15 minutes until thepH is about 3 to give a solid. Stir for 1 hour and collect the solid,wash with ether, and dry under reduced pressure for at 40° C. to givethe title compound as the hydrochloride.

EXAMPLE 410 (5-Bromo-1H-indol-3-yl)acetonitrile

The method of Example 384 using 5-bromoindole gives the title compound:ISMS 234 (M−1); Analysis for C₁₀H₇BrN₂ 0.1H₂O: calcd: C, 50.70; H, 3.06;N, 11.83; found: C, 50.69; H, 2.90; N, 11.64; ¹H NMR (CDCl₃) 8.22 (s,1H), 7.70-7.69 (m, 1H), 7.33-7.31 (m, 1H), 7.24 (s, 1H), 7.23-7.22 (m,1H), 3.78-3.77 (m, 4H).

EXAMPLE 411 5-Bromotryptamine

Dissolve 5-bromo-1H-indole-3-carbonitrile (9.5 g, 40.4 mmol) in 200 mLdry THF and treat with 80 mL 1 M B₃ in THF at ambient temperature. Stirovernight, the reaction and cautiously quench by dropwise addition of 5mL water. Concentrate to dryness under vacuum and the residue. Partitionbetween 1 N HCl and EtOAc. Extract the organic layer with 1 N HCl whichwas combined with the original aqueous layer. The Treat the aqueouslayer with 5 N NaOH and extract with EtOAc. Saturate with NaCl andextract again with EtOAc. Combine the extracts dry over MgSO₄ andconcentrate to dryness to give 4.72 g (19.7 mmol, 49%) of an oil whichcrystallized.

Conversion to the oxalate salt by treating an EtOAc solution of thecompound with a solution of one equivalent of oxalic acid. Filter theresulting solid and dry under vacuum: Analysis for C₁₀H₁₁BrN₂C₂H₂O₂H₂O:calcd: C, 43.08; H, 4.10; N, 8.37; found: C, 43.26; H, 3.91; N, 8.20;ISMS 240 (M+1).

EXAMPLE 413 5-Methoxycarbonyl-1H-indole

Combine 5-carboxyindole (7.2 g, 44.7 mmol) in 400 mL dichloromethane and100 mL MeOH and treat dropwise with 35 mL 2 M TMS diazomethane inhexanes. Stir overnight at ambient temperature. Concentration undervacuum to give the title compound as a solid: Analysis for C₁₀H₉NO₂0.1H₂O: calcd: C, 67.86; H, 5.24; N, 7.91; found: C, 68.03; H, 5.15; N,7.98; ¹H NMR (CDCl₃) 8.44 (bs, 1H), 8.412-8.409 (m, 1H), 7.91-7.88 (m,1H), 7.46-7.38 (m, 1H), 7.26-7.24 (m, 1H), 6.64-6.63 (m, 1H), 3.92 (s,3H); ISMS 176 (M+1).

EXAMPLE 414 3-Formyl-5-methoxycarbonyl-1H-indole

Place anhydrous DMF (25 mL) in a flask under an atmosphere of nitrogen,cool to 10° C. and treat dropwise with POCl₃ (8.22 g, 54 mmol) whilekeeping the temperature below 15° C. Add a solution of5-methoxycarbonyl-1H-indole in 30 mL DMF portionwise keeping thetemperature below 20° C. Remove the cooling bath and stir the mixture atambient temperature for 1 hour then pour onto ice. Addition of 50 mL 5 NNaOH precipitated a solid which is filtered and rinsed with water andEtOAc to give the title compound: ¹H NMR (DMSO-d6) 9.95 (s, 1H), 8.76(s, 1H), 8.4 (s, 1H), 7.9-7.8 (m, 1H), 7.5-7.7 (d, 1H), 3.85 (s, 3H),1.7 (s, 1H); ISMS 204 (M+1).

EXAMPLE 415 3-(2-Nitroethyl)-5-methoxycarbonyl-1H-indole

The method of Example 317 to give the title compound: ¹H NMR (DMSO-d6)12.5 (bs, 1H), 8.38-8.37 (m, 1H), 8.37-8.34 (m, 1H), 8.23 (s, 1H),7.87-7.84 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.55 (d, 1H), 3.85 (s, 3H);ISMS 246 (M+1).

EXAMPLE 416 3-(2-Nitroethyl)-5-methoxycarbonyl-1H-indole

Treat a solution of 3-(2-nitrovinyl)-5-methoxycarbonyl-1H-indole (57 mg,0.23 mmol) in 9 mL THF and 2 mL MeOH with NaBH₄ (26 mg, 0.69 mmol). Stirat ambient temperature overnight, concentrate to dryness and partitionbetween conc. NH₄OH (10 mL) and dichloromethane. Extract the aqueouslayer with dichloromethane, acidify with conc. HCl and extract twicewith dichloromethane. Combine the organic layers, concentrate, andchromatograph on silica gel eluting with 1% MeOH in CHCl₃ to give thetitle compound as a solid: ¹H NMR (CDCl₃) 8.35 (bs, 1H), 8.32 (s, 1H),7.92-7.90 (m, 1H), 7.38-7.36 (d, 1H), 7.12-7.11 (m, 1H), 4.69-4.65 (t,2H), 3.93 (s, 3H), 3.51-3.48 (t, 2H); ISMS 248 (M+).

EXAMPLE 417 5-Methoxycarbonyltryptamine

Combine 3-(2-nitroethyl)-5-methoxycarbonyl-1H-indole (280 mg, 1.1 mmol),PtO₂ (200 mg) and 15 mL MeOH and hydrogenate at atmospheric pressureovernight. Filter reaction mixture through a pad of celite, concentratethe filtrate, and chromatograph on silica gel eluting with 5% MeOH inCHCl₃ mixed with conc. NH₄OH to give the title compound as an oil: ISMS219 (M+1); ¹H NMR (CDCl₃) 9.01 (s, 1H), 8.36 (s, 1H), 7.88-7.85 (m, 1H),7.32-7.24 (m, 1H), 7.05 (s, 1H), 3.91 (s, 3H), 3.05-3.01 (m, 2H),2.93-2.89 (m, 2H), 1.22 (bs, 2H).

EXAMPLE 418 2-(2-(5-Benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine 5-benzyloxytryptamine hydrochloride (1 g, 3.3 mmol), phthalicanhydride (0.56 g, 4.0 mmol) and N,N-diisopropylethylamine (0.86 g, 6.6mmol) in 25 mL anhydrous pyridine and reflux for 1 hour, cool to roomtemperature and treat with 4 g 3 Å molecular sieves. Refluxing wascontinued for 60 hours then the mixture was filtered. Concentrate undervacuum to give a residue which is mixed with 25 mL CHCl₃ and filtered togive a solid. Purification of the filtrate by chromatography on silicagel eluting with 1% MeOH in CHCl₃ to give an additional amount of titlecompound: ISMS 397 (M+1); Analysis for C₂₅H₂₀N₂O₃ 0.3H₂O C₇H₈: calcd: C,75.09; H, 5.25; N, 6.82; found: C, 75.00; H, 5.22; N, 6.96.

By the method of Example 418 the following compounds were prepared: a)2-(2-(5-Hydroxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione: (4.5 mmol,95%); ¹H NMR (DMSO-d6) 10.47 (s, 1H), 8.59 (bs, 1H), 7.84-7.78 (m, 4H),7.09-7.06 (d, 1H), 7.03-7.02 (d, 1H), 6.85-6.84 (d, 1H), 6.56-6.54 (m,1H), 3.79-3.75 (t, 2H), 2.91-2.87 (m, 2H).

EXAMPLE 4192-(2-(5-Hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine a mixture of an oil dispersion of KH (40%, 1 g) in 30 mLanhydrous THF and a suspension of2-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.2 g, 3mmol) in 30 mL THF portionwise. Stir for 1 hour at ambient temperature,cooled to 0° C., add triisopropylsilyltrifluoromethanesulfonate (1.85 g,6 mmol) and stir an additional 1 hour at ambient temperature. Pour thereaction into a rapidly stirring solution of saturated NaHCO₃ andextract with 2×50 mL EtOAc. Combine the organic layer, dry over MgSO₄and concentrate to dryness and chromatograph on silica gel eluting with1% MeOH in CHCl₃ to give2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dioneas an oil.

Combine2-(2-(5-benzyloxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dioneand EtOAc (40 mL) and hydrogenated overnight with 1 g 5% Pd/C atatmospheric pressure. Filter through celite, concentrate to dryness, andchromatograph on silica gel eluting stepwise with a gradient 10% EtOAcin hexanes to 30% EtOAc in hexanes to give the title compound as asolid: FDMS 462 (M+1) Analysis for C₂₇H₂₄N₂O₃Si H₂O: calcd: C, 69.55; H,7.44; N, 6.01; Found: C, 69.44; H, 7.17; N, 6.00.

EXAMPLE 4202-(2-(5-Propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine2-(2-(5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione(0.7 g, 1.5 mmol), cesium carbonate (1 g, 3 mmol) and 1-iodopropane (0.4g, 2.3 mmol) in DMF (25 mL) and stir at ambient temperature overnight.Pour the reaction mixture into 50% EtOAc in hexanes and wash three timeswith brine. Dry the organic layer over MgSO₄ and concentrate undervacuum to give an oil. Chromatograph the oil on silica gel eluting with5% EtOAc in hexanes to give the title compound: ISMS 505 (M+1); ¹H NMR(CDCl₃) 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d, 1H),7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96 (m, 4H),3.12-3.08 (m, 2H), 1.86-1.81 (in 2H), 1.64-1.57 (m, 3H), 1.08-1.04 (m,21H).

EXAMPLE 421 5-Propoxy-1-triisopropylsilanyltryptamine

Combine2-(2-(5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione(416 mg, 0.8 mmol) in 20 mL EtOH and 1 mL hydrazine hydrate. Reflux for3 hours, filter through celite and concentrate to residue. Dissolve theresidue in 10 mL MeOH and load onto a 12 g SCX ion exchange cartridgeand rinse sequentially with MeOH, DMF, then MeOH. Elute the product with2 M N3 in MeOH to give the title compound as an oil: ISMS 375 (M+1); ¹HNMR (CDCl₃) 7.34-7.32 (d, 1H), 7.02 (s, 1H), 7.00-6.99 (d, 1H),6.80-6.77 (m, 1H), 3.97-3.94 (m, 2H), 3.01-2.98 (m, 2H), 2.86-2.83 (m,2H), 1.88-1.76 (m, 2H), 1.70-1.58 (m, 3H), 1.3 (bs, 2H), 1.14-1.08 (m,18H), 1.06-1.02 (t, 3H).

EXAMPLE 422 6-Benzyloxytryptamine

Add to a mixture of LAH (6.2 g, 163.1 mmol) and 300 mL dry THF asolution of 3-(2-nitrovinyl)-6-benzyloxy-1H-indole (9 g, 30.6 mmol) in200 mL THF. Reflux the mixture overnight and then cool to 0° C. andquench sequentially with 6.2 mL water, 6.2 mL 15% aqueous NaOH and 18.6mL water. After stirring 2 hours, filter through celite and concentrateto give 7.9 g (96%) of the title compound as an oil: ¹H NMR (CDCl₃) 8.06(bs, 1H), 7.47-7.43 (m, 3H), 7.38-7.35 (m, 2H), 7.32-7.28 (m, 1H),6.88-6.84 (m, 3H), 5.08 (s, 2H), 3.01-2.97 (m, 2H), 2.87-2.83 (m, 2H),1.6 (bs, 2H).

EXAMPLE 423 N-t-Butoxycarbonyl-2-(6-benzyloxy-1H-indol-3-yl)ethylamine

The method of Example 20 gives the title compound: ¹H NMR (CDCl₃) 7.84(bs, 1H), 9.36 (s, 2H), 8.91 (s, 1H), 7.38-7.33 (m, 2H), 7.28-7.26 (m,1H), 7.20-7.18 (m, 1H), 7.09-7.07 (m, 1H), 6.94-6.93 (m, 1H), 6.68-6.67(m, 1H), 6.50-6.47 (m, 1H), 4.79-4.72 (m, 2H), 4.13 (s, 2H), 3.05-3.02(m, 4H).

EXAMPLE 425 N-t-Butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine

The method of Example 471 gives the title compound.

EXAMPLE 428 2-(2-(5-Ethoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine 2-(2-(5-hydroxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione (900 mg,2.9 mmol), cesium carbonate (960 mg, 2.9 mmol) and 1-iodoethane (920 mg,5.9 mmol) in N-methylpyrrolidinone (5 mL) and stir at ambienttemperature for 4 hours, pour into brine and extract twice with EtOAc.Wash the combined extracts three times with brine, dry over MgSO₄, andconcentrate under vacuum to give an oil. Chromatograph the oil on silicagel eluting with 20% EtOAc in hexanes to give the title compound as awhite solid: ISMS 335 (M+1); Analysis for C₂₀H)₈N₂O₃: calcd: C, 71.84;H, 5.43; N, 8.38; found: C, 71.97; H, 5.47; N, 8.36.

By the method of Example 428 the following compounds were prepared:

a) 2-(2-(5-Isopropoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione: ISMS 348(M+) ¹H NMR (CDCl₃) 7.94 (bs, 1H), 7.82-7.80 (m, 2H), 7.70-7.67 (m, 2H),7.21-7.19 (d, 1H), 7.18 (s, 1H), 7.05-7.04 (d, 1H), 6.82-6.79 (m, 1H),4.55-4.49 (m, 1H), 3.99-3.95 (m, 2H), 3.11-3.07 (m, 2H), 1.64-1.33 (d,6H);

b)2-(2-(5-(2,2,2-Trifluoroethoxy)-1H-indol-3-yl)ethyl)isoindole-1,3-dione:ISMS 389 (M+1); Analysis for C₂₀H₁₅F₃N₂O₃: calcd: C, 61.86; H, 3.89; N,7.21; found: C, 61.77; H, 3.83; N, 7.20;

c) 2-(2-(5-Butoxy-1H-indol-3-yl)ethyl)isoindole-1,3-dione: ISMS 363(M+1); Analysis for C₂₂H₂₂N₂O₃: calcd: C, 72.91; H, 6.11; N, 7.73;found: C, 72.76; H, 6.09; N, 7.42; ¹H NMR (CDCl₃) 7.86-7.81 (m, 3H),7.72-7.68 (m, 2H), 7.23-7.20 (m, 1H), 7.16-7.15 (m, 1H), 7.08-7.07 (m,1H), 6.85-6.84 (m, 1H), 6.4.02-3.98 (m, 4H), 3.13-3.09 (m, 2H),1.83-1.76 (m, 2H), 1.56-148 (m, 2H), 1.01-0.98 (t, 3H);

d) 2-(2-(5-Nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione: ISMS 334(M−1); Analysis for C₁₈H₁₃N₃O₄ 0.1H₂O: calcd: C, 64.13; H, 3.95; N,12.47; found: C, 64.05; H, 3.82; N, 12.27.

By the method of Example 421 the following compounds were prepared:

a) 5-Ethoxytryptamine: ISMS 205 (M+1); Analysis for C₁₂H₁₆N₂O H₂O:calcd: C, 69.33; H, 7.95; N, 13.48; found: C, 69.62; H, 7.75; N, 13.30;

b) 5-Isopropoxytryptamine: ISMS 219 (M+1); ¹H NMR (CDCl₃) 8.57 (bs, 1H),7.20-7.18 (d, 1H), 7.08-7.07 (d, 1H), 6.95 (s, 1H), 6.84-6.82 (m, 1H),4.54-4.48 (m, 1H), 3.01-2.98 (m, 2H), 2.86-2.83 (m, 2H), 1.38 (bs, 2H),1.35-1.33 (d, 6H);

c) 5-(2,2,2-Trifluoroethoxy)tryptamine: ISMS 258 (M+); ¹H NMR (CDCl₃)9.33 (bs, 1H), 7.26-7.24 (d, 1H), 7.09-7.08 (d, 1H), 7.03-7.02 (m, 1H),6.90-6.87 (m, 1H), 4.40-4.34 (m, 2H), 3.03-3.00 (m, 2H), 2.87-2.84 (m,2H), 1.44 (bs, 2H);

d) 5-Butyloxytryptamine: ¹H NMR (CDCl₃) 8.08 (bs, 1H), 7.23-7.21 (d,1H), 7.03-7.02 (d, 1H), 7.03-7.02 (m, 1H), 6.98-6.83 (m, 1H), 4.01-3.98(m, 2H), 3.02-2.99 (m, 2H), 2.87-2.84 (m, 2H), 1.82-1.74 (m, 2H),1.56-1.50 (m, 2H), 1.32 (bs, 2H) 1.00-0.96 (t, 3H);

EXAMPLE 429 5-Benzenesulfonyl-1H-indole

Place a 35% oil dispersion of KH (6 g) in a flask under nitrogen, rinsewith 50 mL hexanes and dry under vacuum. Cool the solid suspension in100 mL anhydrous DMF to 0° C. Add dropwise over 10 minutes a solution of5-bromoindolc (10.3 g, 52.5 mmol) in 25 mL DMF. Stir the mixture 1 hourat 0° C. then treat with triisopropylsilyltrifluoromethane sulfonate(32.2 g, 105.1 mmol). Remove the cooling bath and stir the reaction 72hours before pouring into 500 mL water and extracting with EtOAc. Dilutethe combined extracts with hexanes, wash with brine then dry over MgSO₄.Concentration under vacuum and chromatograph on silica gel eluting with1% EtOAc in hexanes to give 5-Bromo-1-triisopropylsilanyl-1H-indole as acolorless oil: ¹H NMR (CDCl₃) 7.73-7.72 (d, 1H), 7.36-7.34 (d, 1H),7.24-7.23 (d, 1H), 7.21-7.19 (m, 1H), 6.55-6.54 (m, 1H), 1.72-1.61 (m,3H), 1.13-1.10 (m, 18H).

Cool a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (9 g, 25.5mmol) in 550 mL anhydrous THF to −75° C. under argon and treat with 1.7M t-butyl lithium (33 mL, 56.2 mmol) while keeping the temperature below60° C. After the addition, recool the reaction mixture to about −73° C.before adding a solution of phenylsulfonyl fluoride (4.6 g, 28.7 mmol)in 30 mL THF. Stir the reaction at −78° C. for 1 hour then quench withsaturated NaHCO₃ followed by brine. Separate the layers and extract theaqueous layer with EtOAc. Treat the combined organic layers with 1 Mtetrabutylammonium fluoride (35 mL) in THF for 1 hour at ambienttemperature, then concentrate to dryness. Combine the residue withEtOAc, wash twice with 1 N HCl, dry over MgSO₄, and concentrate to anoil. Chromatograph the oil on silica get eluting stepwise with 50% CHCl₃in hexanes followed by 50% CHCl₃ in MeOH give an oily solid. Trituratethe oily solid with CHCl₃ to give the title compound as a solid:Analysis for C₁₄H₁₁NO₂S H₂O: calcd: C, 64.89; H, 4.36; N, 5.41; found:C, 64.76; H, 4.45; N, 5.33; ISMS 257 (M+).

EXAMPLE 430 2-(2-(5-Amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine a mixture of2-(2-(5-nitro-1H-indol-3-yl)ethyl)isoindole-1,3-dione (1.8 g, 5.4 mmol),PtO₂ (500 mg), 100 mL MeOH and 100 mL THF and hydrogenate at atmosphericpressure overnight. Filter the reaction through a pad of celite andconcentrate to dryness. Redissolve the residue in 50/50chloroform/dichloromethane and refilter through a pad of celite.Concentration under vacuum give the title compound as a dark solid: ISMS306 (M+1); Analysis for C₁₈H₁₃N₃O₄ 0.1C₇H₈ 0.2 dichloromethane: calcd:C, 68.70; H, 4.89; N, 12.58; found: C, 69.08; H, 4.75; N, 12.69; ¹H NMR(CDCl₃) 7.9-7.8 (m, 3H), 7.75-7.65 (m, 2H), 7.2-7.1 (m, 1H), 7.05-7.0(m, 2H), 6.7-6.6 (m, 1H), 4.0-3.9 (m, 2H), 3.4 (bs, 2H), 3.1-3.0 (m,2H).

EXAMPLE 431 2-(2-(5-Benzoylamino-1H-indol-3-yl)ethyl)isoindole-1,3-dione

Combine 2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g,1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in30 mL dichloromethane and cool to 0° C. Treat the reaction mixture withbenzoyl chloride (276 mg, 1.96 mmol) and stir overnight during which thetemperature was allowed to warm to room temperature. Concentrate toresidue and chromatograph the residue on silica gel eluting with 0.5%MeOH in CHCl₃ to give the title compound as a solid: ISMS 410 (M+1); ¹HNMR (CDCl₃) 7.86-7.85 (m, 2H), 7.79 (s, 1H), 7.72-7.68 (m, 2H),7.60-7.57 (m, 2H), 7.46-7.42 (m, 1H), 7.4-7.36 (m, 3H), 7.13-7.11 (d,1H), 6.89-6.88 (m, 1H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).

By the method of Example 431 the following compounds were prepared:

a) 2-(2-(5-Methanesulfonylamino-1H-indol-3-yl)ethyl)isoindole-1,3-dione:ISMS 384 (M+1); ¹H NMR (CDCl₃) 10.84 (s, 1H), 9.21 (s, 1H), 7.83-7.76(m, 4H), 7.39-7.38 (m, 1H), 7.27-7.24 (m, 1H), 7.17-7.16 (m, 1H),6.96-6.93 (m, 1H), 3.83-3.80 (m, 2H), 2.98-2.94 (m, 2H), 2.79 (s, 3H),3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).

By the method of Example 421 the following compounds were prepared:

a) 5-Benzoylaminotryptamine: ¹H NMR (CD₃OD) 7.94-7.92 (m, 2H), 7.85 (s,1H), 7.54-7.47 (m, 3H), 7.34-7.29 (m, 2H), 7.08 (s, 1H), 4.86 (s, 2H),3.33 (s, 2H), 2.95-2.86 (m, 4H); and

b) 5-Methanesulfonylaminotryptamine: ISMS 253 (M+); ¹H NMR (CD₃OD)7.46-7.45 (d, 1H), 7.31-7.28 (d, 1H), 7.08 (s, 1H), 7.04-7.01 (m, 1H),4.86 (s, 4H), 2.89-2.83 (m, 7H).

EXAMPLE 432 5-Ethoxycarbonyl-1H-indole

Combine 5-carboxyindole (4.8 g, 29.8 mmol) in 150 mL THF andcarbonyldiimidazole (9.7 g, 59.6 mmol) and stir overnight at ambienttemperature. Treat the reaction mixture with 25 mL EtOH and 1.2 g (29.8mmol) of a 60% oil dispersion of NaH and stir for 2 hours. Concentrationunder vacuum gives a residue. Partition the residue between 150 mL EtOAcand 100 mL brine. Separate the layers, dry the organic layer over MgSO₄,filter, and concentrated to an oil. Chromatograph on silica gel elutingwith 1% MeOH in CHCl₃ to give 7.2 g of an oil. Crystallize the oil fromtoluene gives the title compound: Analysis for C₁₁H₁₁NO₂: calcd: C,69.83; H, 5.86; N, 7.40; found: C, 69.82; H, 5.90; N, 7.38; ISMS 190(M+1).

EXAMPLE 433 5-(N-Butylamido)-1H-indole

Dissolve mixture of 5-carboxyindole (5 g, 31 mmol) in 150 mL THF andtreat with carbonyldiimidazole (5 g, 31 mmol) and stir overnight atambient temperature. Treat the reaction mixture with n-butylamine 4.5 g(62 mmol) and reflux for 1 hour. Concentration under vacuum gives aresidue which is dissolved in EtOAc. Wash sequentially with 5 N HCl, 5 NNaOH, and then brine. Dry the organic layer over MgSO₄ and concentratedto give the title compound as an oil: ¹H NMR (CDCl₃) 8.54 (bs, 1H),8.07-8.06 (m, 1H), 7.63-7.61 (m, 1H), 7.39-7.37 (m, 1H), 7.26-7.24 (m,1H), 6.60-6.59 (m, 1H), 6.14 (bs, 1H), 3.5-3.45 (m, 2H), 1.64-1.57 (m,2H), 1.47-1.37 (m, 2H), 0.97-0.93 (m, 3H); EIMS 217 (M+1).

EXAMPLE 434 5-(N-Propylamido)-1H-indole

The method of Example 433 gives the title compound: ¹H NMR (CDCl₃) 8.07(bs, 1H), 8.07 (s, 1H), 7.63-7.60 (m, 1H), 7.38-7.36 (m, 1H), 7.25-7.24(m, 1H), 6.59-6.58 (m, 1H), 6.21 (bs, 1H), 3.46-3.41 (m, 2H), 1.69-1.60(m, 2H), 1.00-0.96 (m, 3H); EIMS 203 (M+1).

By the method of Example 414 the following compounds were prepared:

a) 3-Formyl-5-benzenesulfonyl-1H-indole: ISMS 286 (M+1); ¹H NMR(DMSO-d6) 9.83 (s, 1H), 8.55 (s, 1H), 7.89-7.86 (m, 2H), 7.61 (s, 2H),7.59-7.52 (m, 3H), 1.70 (s, 3H).

b) 3-Formyl-5-ethoxycarbonyl-1H-indole: Analysis for C₁₂H₁₁NO₃: calcd:C, 66.35; H, 5.10; N, 6.45; found: C, 65.97; H, 5.17; N, 6.46; ISMS 218(M+1);

c) 3-Formyl-N-butylamido-1H-indole: Analysis for C₁₄H₁₆N₂O₂ 0.1H₂O:calcd: C, 68.33; H, 6.64; N, 11.38; found: C, 68.35; H, 6.24; N, 11.30;ISMS 245 (M+1);

d) 3-Formyl-5-(N-propylamido)-1H-indole: Analysis for C₁₃H₁₄N₂O₂: calcd:C, 67.81; H, 6.13; N, 12.16; found: C, 67.42; H, 6.04; N, 12.10; ¹H NMR(DMSO-d6) 9.95 (s, 1H), 8.6 (s, 1H), 8.48-8.45 (t, 1H), 8.36-8.35 (m,1H), 7.76-7.73 (m, 1H), 7.52-7.50 (d, 1H), 3.32 (bs, 1H), 3.24-3.19 (m,2H), 1.58-1.48 (m, 2H), 0.90-0.86 (m, 3H); EIMS 230 (M+);

e) 3-Formyl-6-benzyloxy-1H-indole: ¹H NMR (DMSO-d6) 11.93 (s, 1H), 9.83(s, 1H), 8.12-8.11 (m, 1H), 7.92-7.90 (m, 1H), 7.45-7.27 (m, 5H),7.04-7.03 (m, 1H), 6.92-6.89 (m; 1H), 5.11 (s, 2H).

By the method of Example 415 the following compounds were prepared: a)5-Benzenesulfonyl-3-(2-nitrovinyl)-1H-indole: Analysis for C₁₆H₁₂N₂O₄S0.1H₂O: calcd: C, 58.42; H, 3.83; N, 8.31; found: C, 58.63; H, 3.52; N,8.02; ISMS 229 (M+1);

b) 3-(2-Nitrovinyl)-5-ethoxycarbonyl-1H-indole: Analysis for C₁₆H₁₂N₂O₄S0.1H₂O: calcd: C, 58.42; H, 3.83; N, 8.31; found: C, 58.63; H, 3.52; N,8.02; ISMS 229 (M+1);

c) 3-(2-Nitro-vinyl)-N-butylamido-1H-indole: Analysis for C₁₅H₁₇N₃O₃:calcd: C, 62.71; H, 5.96; N, 14.62; found: C, 62.46; H, 5.81; N, 14.38;ISMS 288 (M+1);

d) 3-(2-Nitro-vinyl)-N-propylamido 1H-indole: ISMS 273 M(+1); ¹H NR(DMSO-d6) 12.38 (s, 1H), 8.62-8.59 (t, 1H), 8.43-8.39 (d, 1H), 8.37 (s,1H), 8.31-8.30 (d, 1H), 8.18-8.15 (d, 1H), 7.84-7.82 (m, 1H), 7.55-7.53(d, 1H), 3.31-3.24 (m, 2H), 1.61-1.52 (m, 2H), 0.92-0.89 (t, 3H);Analysis for C₁₄H₁₅N₃O₃ 0.1H₂O: calcd: C, 61.12; H, 5.57; N, 15.28;found: C, 61.06; H, 5.38; N, 15.05;

e) 3-(2-Nitro-vinyl)-6-benzyloxy-1H-indole: ¹H NMR (DMSO-d6) 11.85 (bs,1H), 8.32-8.29 (m, 1H), 8.09 (s, 1H), 7.94-7.91 (m, 1H), 7.83-7.81 (m,1H), 7.45-7.43 (m, 2H), 7.38-7.31 (m, 2H), 7.29-7.27 (m, 1H), 7.05-7.04(m, 1H), 6.92-6.89 (m, 1H), 5.13 (s, 2H).

By the method of Example 416 the following compounds were prepared:

a) 5-Benzenesulfonyl-3-(2-nitroethyl)-1H-indole: Analysis forC₁₆H₁₄N₂O₄S 0.1H₂O: calcd: C, 57.85; H, 4.31; N, 8.43; found: C, 57.72;H, 4.22; N, 8.25; ISMS 329 (M−1);

b) 3-(2-Nitroethyl)-5-ethoxycarbonyl-1H-indole: Analysis for C₁₃H₁₄N₂O₄:calcd: C, 59.54; H, 5.38; N, 10.68; found: C, 59.23; H, 5.25; N, 10.53;ISMS 263 (M+1),

c) 3-(2-Nitroethyl)-N-butylamido-1H-indole: Analysis for C₁₅H₁₉N₃O₃:calcd: C, 62.27; H, 6.62; N, 14.52; found: C, 61.98; H, 6.39; N, 14.42:ISMS 290 (M+1); and

d) 3-(2-Nitroethyl)-N-propylamido-1H-indole: ¹H NMR (CDCl₃) 8.52 (bs,1H), 8.06 (s, 1H), 7.58-7.55 (m, 1H), 7.35-7.33 (m, 1H), 7.10-7.09 (m,1H), 6.23 (bs, 1H), 4.65-4.61 (t, 2H), 3.48-3.43 (m, 4H), 1.71-1.62 (m,2H), 1.01-0.98 (t, 3H); Analysis for C₁₄H₁₇N₃O₃ 0.1H₂O: calcd: C, 60.68;H, 6.26; N, 15.16; found: C, 60.88; H, 6.05; N, 15.07.

By the method of Example 421 the following compounds were prepared:

a) 5-Benzenesulfonyltryptamine: ISMS 301 (M+1); ¹H NMR (HCl-DMSO-d6) (s,1H), 8.3 (s, 1H), 8.2 (bs, 2H), 8.0-8.9 (m, 2H), 7.4-7.2 (m, 5H),7.1-7.0 (m, 1H), 3.2-3.0 (s, 4H);

b) 5-Ethoxycarbonyltryptamine (isolated as the oxalate salt): Analysisfor C₁₃H₁₆N₂O₂C₂H₂O₄: calcd: C, 55.90; H, 5.63; N, 8.69; found: C,56.07; H, 5.54; N, 8.29; ISMS 233 (M+1); and

c) 5-N-Butylamidotryptamine: Analysis for C₁₅H₂₁N₃O 0.3H₂O: calcd: C,68.05; H, 8.22; N, 15.87; found: C, 68.36; H, 8.11; N, 15.49; ISMS 260(M+1); and

d) 5-N-Propylamidotryptamine:(isolated as the oxalate salt): Analysisfor C₁₄H₁₉N₃O C₂H₂O₄ 0.1EtOAc: calcd: C, 57.23; H, 6.38; N, 12.21;found: C, 57.48; H, 6.53; N, 12.12; ¹H NMR (DMSO-d6) 11.2 (s, 1H), 8.4(t, 1H), 8.2 (s, 1H), 7.75-7.65 (m, 1H), 7.6 (bs, 4H), 7.4-7.35 (m, 1H),7.3-7.25 (d, 1H), 3.3-3.2 (m, 2H), δ 3.15-3.0 (m, 4H), 1.6-1.45 (m, 2H),0.9-0.8 (t, 3H); ISMS 246 (M+1).

EXAMPLE 435 N-t-Butoxycarbonyl-2-(6-butoxy-1H-indol-3-yl)ethylamine

Combine N-t-butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine (250mg, 0.9 mmol), cesium carbonate (295 mg, 0.9 mmol) and 1-iodobutane (200mg, 1.1 mmol) and N-methylpyrrolidinone (10 mL) and stir at ambienttemperature for 2 hours and pour into 75 mL brine. Extract the mixturetwice with 25 mL EtOAc. Wash the combined extracts with brine 2×50 mL,dry over MgSO₄, and concentrate under vacuum to give an oil.

Chromatograph the oil on silica gel eluting with 30% EtOAc in hexanes togive the title compound as a solid: ISMS 333 (M+1); Analysis forC₁₉H₂₈N₂O₃: calcd: C, 68.65; H, 8.49; N, 8.43; found: C, 68.83; H, 8.18;N, 8.33.

By the method of Example 435 the following compounds were prepared: a)N-t-Butoxycarbonyl-2-(6-ethoxy-1H-indol-3-yl)ethylamine: ISMS 305 (M+1);Analysis for C₁₇H₂₄N₂O₃: calcd: C, 67.08; H, 7.95; N, 9.20; found: C,66.85; H, 7.79; N, 9.14.

EXAMPLE 436 6-Butoxytryptamine

Combine N-t-butoxycarbonyl-2-(6-butoxy-1H-indol-3-yl)ethylamine (430 mg,1.3 mmol), 1 mL anisole and 5 mL trifluoroacetic acid and stir at roomtemperature for 2 hours. Concentrate the reaction to dryness undervacuum, mix with 10 mL concentrated NH₄OH and extract with 20 mLdichloromethane. Dry the extract over MgSO₄ and concentrated to 300 mgoil (1.3 mmol, 100%).

By the method of Example 436 the following compounds were prepared: a)6-Ethoxytryptamine: ISMS 305 (M+1); Analysis for C₁₇H₂₄N₂O₃: calcd: C,67.08; H, 7.95; N, 9.20; found: C, 66.85; H, 7.79; N, 9.14

EXAMPLE 437N-t-Butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine

Combine N-t-butoxycarbonyl-2-(6-hydroxy-1H-indol-3-yl)ethylamine (750mg, 2.7 mmol) and pyridine (430 mg, 5.4 mmol) in dichloromethane (30 mL)and cool to 0° C. and treat with benzene sulfonyl chloride (480 mg, 2.7mmol). Allow the reaction to warm to room temperature and stirovernight. Concentrate to dryness the mixture under vacuum, mix withdichloromethane and chromatograph on silica gel eluting with 30% EtOAcin hexanes to giveN-t-butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine as anoil: ISMS 415 (M−1); ¹H NMR (CDCl₃) 8.14 (bs, 1H), 7.66-7.62 (m, 2H),7.51-7.47 (m, 1H), 7.40-7.38 (m, 2H), 7.10 (s, 1H), 7.04-7.03 (m, 2H),6.59-6.57 (m, 1H), 4.57 (bs, 1H), 3.40-3.80 (m, 2H), 2.89-2.86 (m, 2H),1.41 (s, 9H).

Place N-t-butoxycarbonyl-2-(6-phenylsulfonate-1H-indol-3-yl)ethylamine(0.5 g, 1.2 mmol) in a flask with a stream of N₂ passing through it andheat to 200° C. overnight and cool to room temperature. Dissolve theresidue in dichloromethane and chromatography on silica gel eluting with2% MeOH in CHCl₃—NH₄OH to give the title compound as an oil.

By the method of Example 425 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 438 5-propoxy phenyl ISMS 401 (M + 1); Analysis forC₂₀H₁₈N₂O₃ 0.1H₂O: calcd: C, 71.17; H, 6.71; N, 6.38; found: C, 71.02;H, 6.54; N, 6.33; ¹H NMR (Free base-CDCl₃) 7.93 (bs, 1H), 7.34-7.30 (m,2H), 7.35-7.28 (m, 2H), 7.12-707 (m, 1H), 7.06-6.96 (m, 6H), 6.89-6.84(m, 2H), 3.97-3.94 (m, 2H), 3.79 (s, 2H), 2.97-2.94 (m, 4H), 1.89-1.7(m, 2H), 1.51 (bs, 1H), 1.07-1.04 (t, 3H)

EXAMPLE 440N-(2-(5-Propoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine

Combine 2-(5-propoxy-1-triisopropylsilanyltryptamine (138 mg, 0.37mmol), 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (87 mg, 1.8 mmol) and1 g 3 Å molecular sieves in 25 mL EtOH and reflux overnight. Decant theliquid into a separate flask, cool to 0° C. and treat with 42 mg (1.1mmol) NaBH₄. Stir the reaction at ambient temperature for 1 hour, treatwith 0.74 mmol of tetrabutylammonium fluoride and stir for an additionalhour. Concentrate under vacuum to give a residue. Chromatograph theresidue on silica gel eluting with 10% MeOH in CHCl₃ to give the titlecompound. Treat the title compound with 10 mL EtOH with 0.25 mL 5 N HCland 40 mL toluene then concentrating gives the hydrochloride of thetitle compound: ISMS 439 (M+1); ¹H NMR (Free base-CDCl₃) 7.89 (bs, 1H),7.23-7.21 (m, 1H), 7.03-7.02 (d, 1H), 6.99-6.98 (d, 1H), 6.94-6.92 (m,1H), 6.89-6.83 (m, 2H), 6.78-6.75 (m, 1H), 6.18-5.90 (m, 1H), 4.29-4.23(m, 2H), 3.95-3.91 (m, 2H), 3.78 (s, 2H), 2.95 (s, 4H), 1.85-1.75 (m,2H), 1.51 (bs, 1H), 1.06-1.03 (t, 3H).

By the method of Example 440 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 441 5-n-propyl 2,2,2-trifluoro ISMS 434 (M + 1); amidoethyl C₂₃H₂₆F₃N₃O₂•HCl•0.8H₂O•0.1C₇H₈: calcd: C, 57.67; H, 6.00; N,8.51; found: C, 57.55; H, 5.77; N, 8.43 442 5-ethoxy 2,2,3,3- ISMS 453(M + 1); C₂₃H₂₇ClF₃N₃O₂: carbonyl tetrafluoro calcd: C, 56.50; H, 5.15;N, 5.73; propyl found: C, 56.26; H, 5.04; N, 5.76 443 5-ethoxy phenylISMS 415 (M + 1); C₂₆H₂₇ClN₂O₃•0.1H₂O: carbonyl calcd: C, 68.97; H,6.06; N, 6.19; found: C, 68.78; H, 5.87; N, 6.19 445 5-phenoxy 2,2,3,3-ISMS 473 (M + 1); tetrafluoro C₂₆H₂₅ClF₄N₂O₂•0.5H₂O: calcd: C, propyl60.29; H, 5.06; N, 5.41; found: C, 60.27; H, 4.81; N, 5.33 (isolated asthe base) 456 H 2,2,2-trifluoro ISMS 349 (M + 1); C₁₉H₂₀ClF₃N₂O•0.2H₂O:ethyl calcd: C, 58.75; H, 5.29; N, 7.21; found: C, 58.62; H, 5.04; N,7.08 457 H 2,2,3,3,3- ISMS 385 (M + 1); C₁₉H₁₈ClF₅N₂O•0.2H₂O:pentafluoro calcd: C, 53.77; H, 4.37; N, 6.60; found: C, propyl 53.81;H, 4.19; N, 6.59 458 5-phenyl phenyl Analysis for C₂₉H₂₆N₂O•HCl•0.2H₂O:calcd: C, 75.95; H, 6.02; N, 6.11; found: C, 76.01; H, 5.92; N, 5.97ISMS 419 (M + 1) 459 5-(4- phenyl Analysis for fluorophenyl)C₂₉H₂₅FN₂O•HCl•0.2H₂O: calcd: C, 73.08; H, 5.58; N, 5.88; found: C,72.99; H, 5.38; N, 5.83 ISMS 437 (M + 1) 460 5-(N- 2,2,2-trifluoroAnalysis for butylamido) ethyl C₂₄H₂₈F₃N₃O₂•HCl•0.7H₂O: calcd: C, 58.05;H, 6.17; N, 8.46; found: C, 57.86; H, 5.98; N, 8.39 ISMS 448 (M + 1) 4615-hydroxy 2,2,2-trifluoro ISMS 365 (M + 1) ethyl ¹H NMR (DMSO-d6) 10.6(bs, 1H), 9.4 (bs, 2H), 8.75 (s, 1H), 7.45-6.6 (m, 7H), 4.9-4.7 (m, 2H),4.2 (bs, 2H), 3.2-2.9 (m, 4H); 462 5-benzyloxy 2,2,3,3,3- Analysis forC₂₇H₂₅F₅N₂O₂•HCl: pentafluoro calcd: C, 58.87; H, 4.95; N, 5.09; propylfound: C, 59.02; H, 4.76; N, 5.1 ISMS 505 (M + 1)4 463 6-benzyloxy2,2,2-trifluoro ISMS 455 (M + 1) ethyl ¹H NMR (CDCl₃-freebase) 7.88 (bs,1H), 7.48-7.45 (m, 3H), 7.41-7.34 (m, 2H), 7.35-7.30 (m, 1H), 7.25- 7.23(m, 1H), 6.95-6.93 (m, 1H), 6.91-6.90 (m, 2H), 6.88-6.86 (m, 2H),6.81-6.79 (m, 1H), 5.10 (s, 2H), 4.31-4.25 (m, 2H), 3.79 (s, 2H), 2.96(s, 4H), 1.65 (bs, 1H) 464 6-benzyloxy 2,2,3,3- ISMS 487 (M + 1)tetrafluoro Analysis for C₂₇H₂₇F₄N₂O₂•HCl: propyl calcd: C, 62.01; H,5.20; N, 5.36; found: C, 61.69; H, 5.07; N, 5.33 465 6-butyloxy2,2,2-trifluoro ¹H NMR (CDCl₃-freebase) 7.86 (bs, 1H), ethyl 7.45-7.43(m, 1H), 7.23-7.19 (m, 1H), 6.94- 6.92 (m, 1H), 6.89-6.88 (m, 1H),6.84-6.75 (m, 4H), 4.29-4.23 (m, 2H), 3.99-3.96 (m, 2H), 3.78 (s, 2H),2.94 (s, 4H), 1.81-1.74 (m, 2H), 1.55-1.45 (m, 3H), 0.99-0.95 (m, 3H);Analysis for C₂₃H₂₇F₃N₂O₂ HCl: calcd: C, 60.46; H, 6.18; N, 6.13; found:C, 60.23; H, 5.99; N, 6.01 466 5-butyloxy 2,2,3,3- Analysis forC₂₄H₂₈F₄N₂O₂•HCl: tetrafluoro calcd: C, 58.96; H, 5.98; N, 5.73; propylfound: C, 58.62; H, 5.96; N, 5.77 ISMS 453 (M + 1) 467 6-ethoxy2,2,2-trifluoro ISMS 393 (M + 1); Analysis for ethyl C₂₁H₂₃F₃N₂O₂ HCl:calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.94; H, 5.58; N, 6.55 4686-phenyl 2,2,2-trifluoro ISMS 505 (M + 1); Analysis for sulfonate ethylC₂₅H₂₃F₃N₂O₄S HCl: calcd: C, 55.51; H, 4.47; N, 5.18; found: C, 55.27;H, 4.41; N, 5.15 469 6-phenyl 2,2,3,3- ISMS 536 (M + 1); Analysis forsulfonate tetrafluoro C₂₆H₂₄F₄N₂O₄S HCl: calcd: C, 54.50; H, propyl4.40; N, 4.89; found: C, 54.63; H, 4.41; N, 4.86 470 6-phenyl phenylISMS 419 (M + 1); Analysis for C₂₆H₂₄F₄N₂O₄S HCl 0.3H₂O: calcd: C,75.65; H, 6.04; N, 6.08; found: C, 75.63; H, 5.89; N, 6.07 470A6-butyloxy 2,2,3,3- Analysis for tetrafluoro C₂₃H₂₇F₃N₂O₂.HCl.HCl: Cald:C, 58.52; propyl H, 6.02; N, 5.69; found: C, 58.15; H, 5.64; N, 5.58.

EXAMPLE 471N-(2-(5-Hydroxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

CombineN-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylaminehydrochloride (295 mg, 0.6 mmol) and 25 mL EtOH and treat with 0.3 mL 5N HCl and 300 mg 5% Pd/C and hydrogenate at atmospheric pressureovernight. Filter the reaction through a pad of celite and concentrateto dryness then chromatograph on silica gel to give the title compound:ISMS 365 (M+1); ¹H NMR (DMSO-d6) 10.6 (bs, 1H), 9.4 (bs, 2H), 8.75 (s,1H), 7.45-6.6 (m, 7H), 4.9-4.7 (m, 2H), 4.2 (bs, 2H), 3.2-2.9 (m, 4H).

By the method of Example 471 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 472 5-hydroxy 2,2,3,3- ISMS 397 (M + 1); Analysis forC₂₀H₂0F₄N₂O₂ tetrafluoro HCl H₂0: calcd: C, 53.28; H, 5.14; N, 6.21;propyl found: C, 53.31; H, 4.91; N, 6.33 473 6-hydroxy 2,2,2-trifluoroISMS 487 (M + 1); ¹H NMR (DMSO-d6) δ10.52 ethyl (bs, 1H), 9.36 (s, 2H),8.91 (s, 1H), 7.38-7.33 (m, 2H), 7.28-7.26 (m, 1H), 7.20-7.18 (m, 1H),7.09-7.07 (m, 1H), 6.94-6.93 (m, 1H), 6.68-6.67 (m, 1H), 6.50-6.47 (m,1H), 4.79-4.72 (m, 2H), 4.13 (s, 2H), 3.05-3.02 (m, 4H) 474 6-hydroxy2,2,3,3- ISMS 397 (M + 1); Analysis for C₂₀H₂₀F₄N₂O₂ tetrafluoro HClH₂O: calcd: C, 53.28; H, 5.14; N, 6.21; propyl found: C, 53.33; H, 4.76;N, 6.12

EXAMPLE 475N-(2-(5-Carboxy-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

CombineN-(2-(5-methoxycarbonyl-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine(200 mg, 0.5 mmol) in 50 mL THF and 1 mL 3 N NaOH. Reflux the mixtureovernight, treat with 0.7 mL 5 N HCl and concentrate to dryness.Chromatograph to give the title compound: ISMS 393 (M+1); Analysis forC₂₀H₁₉F₃N₂O₃ CF₃COOH 1.2C₇H₈ 2.1H₂O: calcd: C, 55.76; H, 5.20; N, 4.28;found: C, 55.51; H, 5.47; N, 4.50.

EXAMPLE 480 3-(3-Fluoropropoxy)benzaldehyde

Combine 1-bromo-3-fluoropropane (10.0 g, 77.1 mmol) and3-hydroxybenzaldehyde (10.4 g, 92.5 mmol) in dimethylformamide (220 mL)and stir at room temperature. Treat with potassium carbonate in portions(21.3 g, 144.2 mmol). Heat the reaction mixture at 100° C. for 36 hours,then pour into a 1:1 mixture of ice water and dichloromethane. Separatethe phases and extract the aqueous layer with additionaldichloromethane. Wash the combined organic extracts sequentially with1.0 N sodium hydroxide, saturated sodium bicarbonate, brine, and thendry over sodium sulfate. Filtration and removal of the solvent in vacuoprovides a residue. Chromatograph the residue on silica gel eluting with40% ethyl acetate in hexanes to give the title compound as a yellow oil:¹H NMR (400 MHz, CDCl₃) 9.98 (s, 1H), 7.50-7.42 (m, 2H), 7.42-7.38 (m,1H), 7.22-7.16 (m, 1H), 4.66 (dt, 2H, J=46.8, 5.8 Hz), 4.17 (t, 2H,J=6.0 Hz), 2.19 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS (APCI): m/e183.1 (M+1).

EXAMPLE 481 2,2-Difluoroethyltosylate

Combine p-toluenesulfonyl chloride (12.9 g, 67.4 mmol) in pyridine (15mL) at room temperature and treat dropwise with 2,2-difluoroethanol (5.0g, 60.9 mmol) via syringe. Stir the reaction mixture under nitrogen for72 hours, partition between water (20 mL) and dichloromethane (20 mL).Separate the aqueous phase and extract with additional dichloromethane(2×40 mL). Combine the organic extracts and wash sequentially with 1 Nhydrochloric acid (2×50 mL), sodium bicarbonate (2×50 mL), and brine(2×50 mL). Dry the organic layer over sodium sulfate and concentrate invacuo to give the title compound as a yellowish oil: ¹H NMR (300 MHz,CDCl₃): 7.82 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=9.0 Hz), 5.92 (tt, 1H,J=55.0, 0.4 Hz), 4.19 (td, 2H, J=12.6, 4.0 Hz), 2.48 (s, 3H).

EXAMPLE 482 3-(2,2-Difluoroethoxy)benzaldehyde

The method of Example 480 gives the title compound as a yellow oil. ¹HNMR (400 MHz, CDCl₃): 9.97 (s, 1H), 7.56-7.44 (m, 2H), 7.41-7.37 (m,1H), 7.21 (ddd, 1H, J=8.0, 2.8, 1.2 Hz), 6.11 (tt, 1H, J=55.0, 4.0 Hz),4.24 (td, 2H, J=12.6, 4.0 Hz).

EXAMPLE 483N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(3-fluoropropoxy)benzylamine

Combine 6-chlorotryptamine (1.4 g, 7.2 mmol),3-(3-fluoropropoxy)benzaldehyde (1.3 g, 7.2 mmol), and molecular sievesin ethanol (150 mL), and heat at 78° C. overnight. Filter the reactionmixture through a plug of celite, and treat the resulting filtrate withsodium borohydride (817 mg, 21.6 mmol) and stir overnight at roomtemperature. Evaporate the solvent in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 9:1 mixture ofdichloromethane and 1N ammonia in methanol to give a residue.Chromatograph that residue on 10 g SCX column (wash column with methanolthen elute with 1 N ammonia in methanol) and concentrate in vacuo togive a light yellow oil. Dissolve the oil in methanol and treated with amethanolic solution of ammonium chloride (112 mg, 2.1 mmol). Sonicatethe resulting mixture for 10 minutes, remove the solvent in vacuo, andtriturate the resulting residue with ether containing a few drops ofacetonitrile to give a solid. Collect the solid by filtration to givethe title compound as the hydrochloride: mp 177.8-178.9° C.; ¹H NMR (400MHz, dmso-d₆): 11.15 (br s, 1H), 9.41 (br s, 2H), 7.57 (d, 1H, J=8.0Hz), 7.39 (d, 1H, J=2.0 Hz), 7.32 (t, 1H, J=7.8 Hz), 7.26 (d, 1H, J=2.4Hz), 7.25-7.21 (m, 1H), 7.11 (d, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.8, 2.0Hz), 6.97 (dd, 1H, J=8.0, 2.0 Hz), 4.60 (dt, 2H, J=47.6, 6.0 Hz), 4.13(br s, 2H), 4.08 (t, 2H, J=6.4 Hz), 3.10 (br s, 4H), 2.11 (dquintuplets, 2H, J=26.0, 6.0 Hz); MS (ES+): m/e 361.3 (M+1); CHN (forC₂₀H₂₂ClFN₂O.HCl) calcd: C, 60.46; H, 5.83; N, 7.05; found: C, 60.48; H,5.86; N, 7.16.

By the method of Example 483 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 484 6-fluoro 3-fluoro mp: 174.8-176.0° C.; ¹H NMR (400MHz, dmso-d6): 11.03 (br s, 1H), 9.35 (br s, 2H), 7.52 (dd, 1H, J=8.8,propyl 5.2 Hz), 7.30 (t, 1H, J=7.8 Hz), 7.22-7.17 (m, 2H), 7.13-7.06 (m,2H), 6.95 (dd, 1H, J=7.8, 2.2 Hz), 6.83 (ddd, 1H, J=9.6, 8.8, 2.4 Hz),4.58 (dt, 2H, J=47.2, 5.8 Hz), 4.11 (s, 2H), 4.06 (t, 2H, J=6.2 Hz),3.08 (br s, 4H), 2.08 (d quintuplets, 2H, J=26.0, 6.0 Hz); MS (ES+): m/e345.3 (M + 1); CHN (for C₂₀H₂₂F₂N₂O HCl) calcd: C 63.07, H 6.09, N 7.36;found: C 62.82, H 6.13, N 7.57 485 6-fluoro 2,2-difluoro mp 165.0-166.5°C. ¹H NMR (400 MHz, dmso-d6): 11.08 (br s, 1H), 7.56 (dd, 1H, J=8.7, 5.2Hz), 7.39-7.31 ethyl (m, 2H), 7.21 (d, 1H, J=2.0 Hz), 7.18 (d, 1H, J=6.9Hz), 7.12 (dd, 1H, J=10.4, 1.7 Hz), 7.04 (dd, 1H, J=8.7, 1.7 Hz),6.89-6.81 (m, 1H), 6.42 (tt, 1H, J=53.9, 3.5 Hz), 4.32 (td, 2H, J=11.3,3.2 Hz), 4.14 (s, 2H), 3.20-3.00 (m, 4H); MS: (ES+): m/e 349.0 (M + 1)486 6-chloro 2,2-difluoro mp 131.6-133° C.: ¹H NMR (400 MHz, dmso-d6):11.15 (br s, 1H), 9.50 (br s, 2H), 7.57 (d, 1H, J=8.8 Hz), 7.39 ethyl(d, 1H, J=2.0 Hz), 7.36 (t, 1H, J=8.2 Hz), 7.32 (br s, 1H), 7.26 (d, 1H,J=2.0 Hz), 7.17 (d, 1H, J=7.6 Hz), 7.04 (dd, 1H, J=7.8, 2.2 Hz), 7.01(dd, 1H, J=8.4, 2.0 Hz), 6.41 (tt, 1H, J=54.4, 3.4 Hz), 4.32 (td, 2H,J=14.8, 3.6 Hz), 4.14 (br s, 2H), 3.11 (br s, 4H); MS (ES+): m/e 365.3(M + 1); CHN (for C₁₉H₁₉F₂ClN₂O•HCl•0.3 H₂0) calcd: C 56.11; H 5.11; N6.89; found: C 56.03; H 4.95; N 7.18 487 6-chloro 2,2,3,3,3- mp199.8-201.1° C.; ¹H NMR (400 MHz, dmso-d6): 11.15 (br s, 1H), 9.35 (brs, 2H), 7.57 (d, 1H, J=8.4 Hz), pentafluoro 7.44-7.32 (m, 3H), 7.26 (d,1H, J=2.0 Hz), 7.22 (d, 1H, J=8.0 Hz), 7.10 (dd, 1H, J=8.4, 2.0 Hz),7.00 (dd, 1H, propyl J=8.6, 1.8 Hz), 4.85 (t, 2H, J=13.2 Hz), 4.13 (s,2H), 3.10 (br s, 4H); MS (ES+): m/e 433.0 (M + 1); CHN (forC₂₀H₁₈ClF₅N₂O•0.97HCl) calcd: C 51.31, H 4.08, N 5.98; found: C 51.61, H4.07, N 6.00 488 5-isopropyl 2,2,3,3,3- mp 168.5-171.0° C.; MS (ES+):m/e 441.1 (M + 1); CHN (for C₂₃H₂₅F₅N₂O•HCl•0.3H₂0) calcd: C 57.28,pentafluoro H 5.56, N 5.81; found: C 57.10, H 5.21, N 6.03 propyl 4895-isopropyl 2,2,3,3- mp 167.0-168.2° C.; ¹H NMR (400 MHz, dmso-d6):10.72 (br s, 1H), 7.44 (t, 1H, J=7.8 Hz), 7.34 (br s, 1H), tetrafluoro7.22-7.15 (m, 2H), 7.14 (br s, 1H Hz), 7.06 (d, 1H, J=7.6 Hz), 7.01 (dd,1H, J=8.4, 1.6 Hz), 6.69 (tt, 1H, J=51.6, propyl 5.6 Hz), 5.86 (s, 1H),4.70-4.50 (m, 2H), 3.50-3.25 (m, 4H, overlapping with H₂O), 3.17-3.05(m, 1H), 3.05-2.91 (m, 2H), 1.24 (d, 6H, J=6.8 Hz); MS (ES+): m/e 422.1(M + 1)

EXAMPLE 490N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-methyl-3-(2,2-difluoroethoxy)benzylamine

CombineN-(2-(6-chloro-1H-indol-3-yl)ethyl)-3-(2,2-difluoroethoxy)benzylamine(276 mg, 0.76 mmol) and formaldehyde (55.5 μL of a 38% aqueous solution,0.76 mmol) in dichloroethane (115 mL) and stir at room temperature for10 minutes; then add in two portions over 10 minutes sodiumtriacetoxyborohydride (321 mg, 1.51 mmol). Stir the reaction mixture atroom temperature overnight and dilute with methanol (10 mL) and quenchwith one drop of glacial acetic acid. Remove the solvent in vacuo, togive a residue, redissolve the crude residue in methanol and directlyload onto a 10 g SCX column. After washing the column thoroughly withmethanol, elute with 2 N ammonia in methanol. Concentrate in vacuo togive the title compound as an oil. Dissolve the oil (239 mg, 0.64 mmol)in methanol (20 mL) and treat with a solution of ammonium chloride (36mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutesbefore removal of the solvent in vacuo to give the title compound as thehydrochloride salt. Dissolve the salt in 10 mL of 1:1 acetonitrile-waterand lyophilize overnight, providing a fluffy white solid. Triturate thesolid with diethyl ether (10 mL) and acetonitrile (2 drops), filter, anddry to give the title compound as the hydrochloride salt: mp: 63.8-65.8°C.; ¹H NMR (400 MHz, dmso-d6): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz)7.36 (d, 1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz),7.20-7.11 (m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4Hz), 6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H,J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): m/e 378.9(M+1.

By the method of Example 490 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 491 6-fluoro 2,2-difluoro mp: 70.8-73.0° C.; ¹H NMR (400MHz, CDCl₃): ethyl 9.01(br s, 1H), 7.40-7.35(m, 1H), 7.35(dd, 1H, J=8.8,5.6 Hz), 7.31-7.25(m, 1H), 7.10-7.02 (m, 2H), 6.97-6.91(m, 2H), 6.77(td,1H, J=9.2, 2.0 Hz), 6.05(tt, 1H, J=54.8, 4.0 Hz), 4.21(td, 2H, J=13.0,4.0 Hz), 4.08(br s, 2H), 3.30-3.18 (m, 2H), 3.18-3.05(m, 2H), 2.66(s,3H); MS (APCI): m/e 363.1 (M + 1) 492 6-fluoro 3-fluoro mp: 66.4-69.3°C.; ¹H NMR (300 MHz, dmso- propyl d₆): 11.04(s, 1H), 11.20-10.70(br s,1H), 7.52 (dd, 1H, J=8.8, 5.5 Hz), 7.34(t, 1H, J=7.9 Hz), 7.30-7.20(m,1H), 7.20(d, 1H, J=2.2 Hz), 7.12(AB_(q), 2H, J_(AB)=22.4 Hz, ΔJ_(AB)=9.8Hz), 7.00(br d, 1H, J=8.4 Hz), 6.84(ddd, 1H, J= 9.9, 8.8, 2.2 Hz),4.61(dt, 2H, J=47.2, 5.9 Hz), 4.44-4.03(br m, 2H), 4.08(t, 2H, J=6.4Hz), 3.17(br s, 4H), 2.68(br s, 3H), 2.11 (dquintuplets, 2H, J=25.6, 6.1hz); MS (ES+): m/e 358.9 (M + 1) 493 6-chloro 3-fluoro mp: 61.4-63.4°C.; ¹H NMR (400 MHz, DMSO- propyl d₆): 11.14(s, 1H), 7.54(d, 1H, J=8.4Hz), 7.40 (d, 1H, J=2.4 Hz), 7.35(t, 1H, J=8.0 Hz), 7.32-7.23(m, 2H),7.13(br d, 1H, J=7.2 Hz), 7.07-7.00(m, 1H), 6.99(dd, 1H, J=8.6, 1.8 Hz),4.60(dt, 2H, J=46.8, 5.8 Hz), 4.50-4.15 (br m, 2H), 4.08(t, 2H, J=6.4Hz), 3.18(br s, 4H), 2.72(br s, 3H), 2.11(dquintuplets, 2H, J= 26.0, 6.4Hz); MS (APCI): m/e 375.1 (M + 1) 494 6-chloro 2,2,3,3,3- mp206.6-207.5° C.; ¹H NMR (400 MHz, pentafluoro methanol-d₄): 7.97(d, 1H,J=8.0 Hz 7.93-7.85 propyl (m, 2H), 7.75-7.68(m, 2H), 7.65(br d, 1H, J=7.2 Hz), 7.58(br d, 1H, J=8.0 Hz), 7.47(br d, 1H, J=9.2 Hz), 5.21(t, 2H,J=13.0 Hz), 4.60 (br s, 2H), 3.61(br s, 4H), 3.14(br s, 3H); MS (ES+):m/e 447.1 (M + 1); CHN (for C₂₁H₂₀ClF₅N₂O•HCl) calcd: C 52.19; H 4.38; N5.80; found: C 52.16; H 4.29; N 5.82

EXAMPLE 495N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-N-isopropyl-3-(2,2,3,3-pentafluoropropoxy)benzylamine

CombineN-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzylamine(254 mg, 0.59 mmol) in 20 mL of 95:5 methanol-acetic acid, treat withacetone (441 μL, 5.9 mmol) followed by sodium cyanoborohydride inportions (148 mg, 2.3 mmol). Stir the reaction mixture at 50° C.overnight; then at room temperature for an additional 2 days. Remove thesolvent in vacuo to give a residue. Chromatograph the residue on silicagel eluting with 4% methanol in dichloromethane to give the titlecompound as a colorless oil. Dissolve the oil (237 mg, 0.49 mmol) inmethanol (15 mL) and treat with a solution of ammonium chloride (27 mg,0.49 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutesbefore concentrating it to a tacky white solid. Dissolve the tacky solidin 10 mL of 1:1 acetonitrile-water and lyophilize to give 241 mg (96%)of the title compound as the hydrochloride: mp: 77.0-80.2° C.; ¹H NMR(400 MHz, methanol-d₄): 7.31 (br t, 1H, J=7.8 Hz), 7.26-7.21 (m, 1H),7.16 (br d, 1H, J=8.4 Hz), 7.15-7.07 (m, 2H), 7.05-6.95 (m, 2H), 6.83(dd, 1H, J=8.0, 2.0 Hz), 4.52 (t, 2H, J=12.8 Hz), 4.12 (br s, 2H), 3.53(br s, 1H), 3.11 (br s, 2H), 2.89 (br s, 2H), 1.27 (br s, 6H); MS(APCI): m/e 475.1 (M+1).

By the method of Example 495 the following compounds were prepared andisolated as the maleate:

No. Z′ R Data 496 6-chloro propyl mp 92.4-94.6° C. Mass (ES+): m/z 475.0(M + 1). Elemental Analysis Calculated forC₂₃H₂₄ClF₅N₂O•1.0C₄H₄O₄•0.5H₂O: C, 53.30; H, 4.93; N, 4.57. Found: C,53.00; H, 4.55; N, 4.86. 497 6-chloro ethyl mp 101.0-1-104.0° C. Mass(ES+): m/z 461.0 (M + 1).

EXAMPLE 500N-(2-(6-Chloro-5-methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxybenzylamine

Combine 5-methoxy-6-chlorotrypatamine (0.2 mmol) in dichloromethane (1mL) and 3-(2,2,3,3-tetrapropylfluororpropoxy)benzaldehyde (0.32 mmol) indichloromethane (1 mL) and rotate. After 2 h, add sodium borohydride(37.83 mg, 1.0 mmol) as a stock solution in dichloromethane (1 mL).After overnight rotation, dilute the reaction mixture with 1 mL ofmethanol, and apply the resulting solution directly to a 2 g SCX column.Thoroughly wash the column with methanol, elute with 2 Mammonia-methanol and concentrate to a residue. If a TLC of eluent,indicates that the reaction was not complete. Dilute the residue withdichloromethane (1 mL) and add a second stock solution of sodiumborohydride (37.83 mg, 1.0 mmol) in 1-methyl-2-pyrrolidinone (1 mL).After rotation for 2 h, dilute the reaction mixture with 1 mL ofmethanol, and directly apply the resulting solution to a 2 g SCX column.Thoroughly wash the column with methanol, elute with 2 Mammonia-methanol and concentrate to a residue. Further purification on aSI column. Elution with straight ethyl acetate. Compound wascharacterized using LC method 1 or 2. LCMS R_(t) 2.749 min at 254 nm,2.800 min at 220 nm; m/e 445 (M+1).

General LC Methods:

Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

Method 2: (Shimadzu) 10-80 in 9 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.08% trifluoroaceticacid. Column: C18 Metachem, monochrom 5 micron, 4.6×50.

The following compounds were prepared in a manner similar to Example 500and isolate as the base unless otherwise indicated:

No. Z′ R₄ Data 501 3-CF₃ 2,2,2- Method 2: LC Rf 3.90 min at 220 nm,trifluoroethyl 3.908 min at 264 nm. 502 3,5-dimethoxy 2,2,2- Method 2:LC Rf 3.620 min at 254 nm, trifluoroethyl 3.62 min at 220 nm, m/e 367(M + 1). 503 3-chloro 2,2,3,3- Method 1: LCMS Rf 2.800 min at 220tetrafluoro nm, m/e 376 (M + 1). propyl 504 3-CF₃ 2,2,3,3- Method 1:LCMS Rf 2.885 min at 254 tetrafluoro nm, m/e 410 (M + 1). propyl 5063-chloro 2-fluoroethyl Method 2: LC Rf 3.420 min at 254 nm, 3.42 min at220 nm. 507 3-trifluoromethyl 2-fluoroethyl Method 2: LC Rf 3.580 min at254 nm, 3.58 min at 220 nm. 508 3,5-dimethoxy 2-fluoroethyl Method 2: LCRf 3.212 min at 254 nm, 3.22 min at 220 nm. 509 3-trifluoromethyl propylMethod 2: LC Rf 3.892 min at 254 nm, 3.89 min at 220 nm. 510 2-chlorophenyl Method 1: LCMS Rf 2.479 min at 2854 nm, m/e 338 (M + 1). 5113-trifluoromethyl phenyl Method 1: LCMS Rf 2.969 min at 254 nm, m/e 372(M + 1).

No. Z′ R₄ Data 512 5-methoxy 6- 2,2,2- Method 1: LCMS Rf 2.651 min at220 chloro trifluoroethyl nm, m/e 413 (M + 1). 513 6-fluoro 2,2,2-Method 1: LCMS Rf 2.618 min at 254 trifluoroethyl nm, 2.700 min at 220nm, m/e 367 (M + 1). 514 4-chloro 2,2,2- Method 1: LCMS Rf 2.683 min at254 5-methoxy trifluoroethyl nm, 2.661 min at 220 nm, m/e 399 (M + 1).515 5-methoxy 2,2,3,3- Method 1: LCMS Rf 2.749 min at 254 6-chlorotetrafluoropropyl nm, 2.800 min at 220 nm, m/e 445 (M + 1). 516 6-fluoro2,2,3,3- Method 1: LCMS Rf 2.683 min at 254 tetrafluoropropyl nm, 2.661min at 220 nm, m/e 399 (M + 1). 517 4-chloro 2,2,3,3- Method 1: LCMS Rf2.682 min at 254 5-methoxy tetrafluoropropyl nm, 2.663 min at 220 nm,m/e 445 (M + 1). 522 5-methoxy 2-fluoroethyl Method 2: LC Rf 3.19 min at220 nm.

EXAMPLE 523N-(2-(6-Trifluoromethyl-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

Combine 5-trifluoromethyltryptamine (0.1 mmol) in methanol (1 mL) and3-phenoxybenzaldehyde (0.2 mmol) in methanol (1 mL) and rotate. After 3h, add sodium borohydride (18 mg, 0.5 mmol) as a stock solution in1-methyl-2-pyrrolidinone (0.5 mL). After overnight rotation, dilute thereaction mixture with 1 mL of methanol, directly apply the resultingsolution to a 2 g SCX column. Wash thoroughly the column with methanol,and elute with 2 M ammonia-methanol and concentrate the eluent. Furtherpurification on SI column eluting with ethyl acetate affords the desiredcompound. Characterization of the compound is achieve by using method 1.LCMS R_(f) 2.954 min at 254 nm, 2.954 min at 220 nm, m/e 411 (M+1).

LC Method:

Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared following a similar procedure asin Example 523 and isolated as the base unless otherwise indicated:

No. Z′ R₄ Data 524 6-trifluoro phenyl Method 1: LCMS Rf 2.954 min at 254nm, methyl 2.954 min at 220 nm, m/e 411 (M + 1). 525 6-fluoro phenylMethod 1: LCMS Rf 2.712 min at 254 nm, 2.712 min at 220 nm, m/e 361 (M +1). 526 5-methoxy phenyl Method 1: LCMS Rf 2.757 min at 254 nm, 6-chloro2.757 min at 220 nm, m/e 407 (M + 1). 527 4-chloro propyl Method 1: LCMSRf 2.578 min at 254 nm, 5-methoxy 2.577 min at 220 nm, m/e 373 (M + 1).528 6-trifluoro propyl Method 1: LCMS Rf 2.850 min at 254 nm, methyl2.849 min at 220 nm, m/e 377 (M + 1). 529 6-fluoro propyl Method 1: LCMSRf 2.576 min at 254 nm, 2.576 min at 220 nm, m/e 327 (M + 1). 5305-methoxy propyl Method 1: LCMS Rf 2.637 min at 220 nm, m/e 6-chloro 373(M + 1).

EXAMPLE 531N-(2-(4-Sulfonamidophenyl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxybenzylamine

Combine 4-sulfonamidophenylethylamine (0.2 mmol) in methanol (1 mL) and3-(2,2,3,3,3-pentapropylfluororpropoxy)benzaldehyde (0.32 mmol) inmethanol (1 mL) and rotate. After 1 hour add sodium borohydride (18 mg,1.0 mmol) as a stock solution in 1-methyl-2-pyrrolidinone (1 mL). Afterovernight rotation, dilute the reaction mixture with 1 mL of methanol,and directly apply the resulting solution to a 2 g SCX column. Afterthoroughly washing with methanol, elute the column with 2 Mammonia-methanol and concentrate the eluent to a residue. Furtherpurification by Gilson UV prep system afforded the desired compound andthe compound was characterized using method 1. LCMS R_(f) 2.345 min at254 nm, 2.347 min at 220 nm, m/e 439 (M+1) 461 (M+22).

LC Method:

Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared using a similar procedure as inExample 531 and isolated as the base unless otherwise indicated:

No. Z′ R₄ Data 532 2,5- 2,2,3,3,3- Method 1: LCMS Rf 2.816 min at 254dimethoxy pentafluoropropyl nm, 2.815 min at 220 nm, m/e 420 (M + 1).533 3,4- 2,2,3,3,3- Method 1: LCMS Rf 2.634 min at 254 dimethoxypentafluoropropyl nm, 2.637 min at 220 nm, m/e 420 (M + 1). 534 4-2,2,3,3- Method 1: LCMS Rf 2.155 min at 254 sulfonamidetetrafluoropropyl nm, 2.156 min at 220 nm, m/e 421 (M + 1). 535 4-3-fluoropropyl Method 1: LCMS Rf 1.816 min at 254 sulfonamide nm, 1.818min at 220 nm, m/e 367 (M + 1), 389 (M + 22). 537 4- 2-fluoroethylMethod 1: LCMS Rf 1.606 min at 254 sulfonamide nm, 1.606 min at 220 nm,m/e 375 (M + 22). 538 3,4- phenyl Method 1: LCMS Rf 2.511 min at 254dimethoxy nm, 2.511 min at 220 nm, m/e 364 (M + 1). 539 4-2,2-difluoroethyl Method 1: LCMS Rf 1.782 min at 254 sulfonamide nm,1.782 min at 220 nm, m/e 371 (M + 1), 393 (M + 22). 540 2,5-2,2-difluoroethyl Method 1: LCMS Rf 2.359 min at 254 dimethoxy nm, m/e352 (M + 1). 541 3,4- 2,2-difluoroethyl Method 1: LCMS Rf 2.085 min at254 dimethoxy nm, 2.070 min at 220 nm, m/e 335 (M + 1), 352 (M + 22).542 4- 2,2-difluoroethyl Method 1: LCMS Rf 1.816 min at 254 sulfonamidenm, 1.818 min at 220 nm, m/e 367 (M + 1), 389 (M + 22). 543 2,5-3-fluoropropyl Method 1: LCMS Rf 2.387 min at 254 dimethoxy nm, 2.381min at 220 nm, m/e 348 (M + 1).

EXAMPLE 545N-(2-(6-Methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxybenzylamine

Combine amine (0.2 mmol) in 1-methyl-2-pyrrolidinone (1 mL) and aldehyde(0.32 mmol) in dichloromethane (1 mL) and rotate. After 1 h, add sodiumborohydride (18 mg, 1.0 mmol) as a stock solution in1-methyl-2-pyrrolidinone (1 mL). After rotation overnight, dilute thereaction mixture with 1 mL of 10% acetic acid/methanol, and directlyapply the resulting solution to a 2 g SCX column. Thoroughly wash withmethanol, elute the column with 2 M ammonia-methanol and concentrate theeluent to a residue, which was further purified by Gilson UV prepsystem. Characterize the compound using method 1. LCMS R_(f) 3.752 minat 254 nm, 3.753 min at 220 nm, m/e 429 (M+1).

LC Method:

Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared by following a similar procedureto Example 545:

No. Z′ R₄ Data 546 4-chloro 2,2,3,3,3- Method 1: LCMS Rf 3.873 min at254 nm, pentafluoro 3.877 min at 220 nm, m/e 433 (M + 1). propyl 5474-methoxy 2,2,3,3,3- Method 1: LCMS Rf 3.828 min at 254 nm, pentafluoro3.833 min at 220 nm, m/e 429 (M + 1). propyl 548 5-methoxy 2,2,3,3,3-Method 1: LCMS Rf 3.802 min at 254 nm, 2-methyl pentafluoro 3.805 min at220 nm, m/e 433 (M + 1). propyl 549 7-methoxy 2,2,3,3,3- Method 1: LCMSRf 3.800 min at 254 nm, pentafluoro 3.806 min at 220 nm, m/e 429 (M +1). propyl 550 6-chloro 2,2,3,3,3- Method 1: LCMS Rf 3.947 min at 254nm, pentafluoro 3.952 min at 220 nm, m/e 433 (M + 1). propyl 5514-methoxy 2,2,3,3- Method 1: LCMS Rf 3.695 min at 254 nm, tetrafluoro3.695 min at 220 nm, m/e 411 (M + 1). propyl 552 5-methoxy 2,2,3,3-Method 1: LCMS Rf 3.654 min at 254 nm, 2-methyl tetrafluoro 3.654 min at220 nm, m/e 425 (M + 1). propyl 553 7-methoxy 2,2,3,3- Method 1: LCMS Rf3.659 min at 254 nm, tetrafluoro 3.661 min at 220 nm, m/e 411 (M + 1).propyl 554 6-chloro 2,2,3,3- Method 1: LCMS Rf 3.821 min at 254 nm,tetrafluoro 3.821 min at 220 nm, m/e 415 (M + 1). propyl 555 6-methoxy2-fluoroethyl Method 1: LCMS Rf 3.169 min at 254 nm, 3.169 min at 220nm, m/e 345 (M + 1). 556 4-chloro 2-fluoroethyl Method 1: LCMS Rf 3.411min at 254 nm, 3.412 min at 220 nm, m/e 347 (M + 1). 557 4-methoxy2-fluoroethyl Method 1: LCMS Rf 3.303 min at 254 nm, 3.304 min at 220nm, m/e 343 (M + 1). 558 5-methoxy 2-fluoroethyl Method 1: LCMS Rf 3.236min at 254 nm, 2-methyl 3.236 min at 220 nm, m/e 357 (M + 1). 5597-methoxy 2-fluoroethyl Method 1: LCMS Rf 3.263 min at 254 nm, 3.264 minat 220 nm, m/e 343 (M + 1). 560 6-chloro 2-fluoroethyl Method 1: LCMS Rf3.465 min at 254 nm, 3.466 min at 220 nm, m/e 347 (M + 1). 561 6-methoxy2,2- Method 1: LCMS Rf 3.190 min at 254 nm, difluoroethyl 3.190 min at220 nm. 562 6-chloro phenyl Method 1: LCMS Rf 3.795 min at 254 nm, 3.795min at 220 nm, m/e 377 (M + 1). 563 6-fluoro 2-fluoroethyl Method 1:LCMS Rf 3.305 min at 254 nm, 3.306 min at 220 nm, m/e 331 (M + 1). 5714-chloro propyl Method 1: LCMS Rf 3.668 min at 254 nm, 3.668 min at 220nm, m/e 343 (M + 1). 572 4-methoxy propyl Method 1: LCMS Rf 3.581 min at254 nm, 3.582 min at 220 nm, m/e 339 (M + 1). 573 5-methoxy propylMethod 1: LCMS Rf 3.524 min at 254 nm, 2-methyl 3.524 min at 220 nm, m/e353 (M + 1). 574 7-methoxy propyl Method 1: LCMS Rf 3.553 min at 254 nm,3.554 min at 220 nm, m/e 339 (M + 1). 575 6-chloro propyl Method 1: LCMSRf 3.736 min at 254 nm, 3.736 min at 220 nm, m/e 343 (M + 1). 576 4,6-phenyl Method 1: LCMS Rf 3.830 min at 254 nm, difluoro 3.832 min at 220nm, m/e 423 (M + 1). 5-methoxy 577 6-methoxy phenyl Method 1: LCMS Rf3.527 min at 254 nm 3.531 min at 220 nm, m/e 373 (M + 1). 578 4-chlorophenyl Method 1: LCMS Rf 3.749 min at 254 nm, 3.749 min at 220 nm, m/e377 (M + 1). 579 4-methoxy phenyl Method 1: LCMS Rf 3.657 min at 254 nm,3.658 min at 220 nm, m/e 373 (M + 1). 580 5-methoxy- phenyl Method 1:LCMS Rf 3.609 min at 254 nm, 2-methyl 3.609 min at 220 nm, m/e 3387 (M +1). 581 7-methoxy phenyl Method 1: LCMS Rf 3.622 min at 254 nm, 3.622min at 220 nm, m/e 373 (M + 1). 582 6-chloro phenyl Method 1: LCMS Rf3.795 min at 254 nm, 3.795 min at 220 nm, m/e 377 (M + 1). 583 4,6-2,2-difluoro Method 1: LCMS Rf 3.514 min at 254 nm, difluoro ethyl 3.519min at 220 nm, m/e 411 (M + 1). 5-methoxy 585 4-chloro 2,2-difluoroMethod 1: LCMS Rf 3.418 min at 254 nm, ethyl 3.419 min at 220 nm, m/e365 (M + 1). 586 4-methoxy 2,2-difluoro Method 1: LCMS Rf 3.301 min at254 nm, ethyl 3.305 min at 220 nm, m/e 361 (M + 1). 587 5-methoxy-2,2-difluoro Method 1: LCMS Rf 3.269 min at 254 nm, 2-methyl ethyl 3.269min at 220 nm, m/e 375 (M + 1). 588 7-methoxy 2,2-difluoro Method 1:LCMS Rf 3.265 min at 254 nm, ethyl 3.271 min at 220 nm, m/e 361 (M + 1).589 6-chloro 2,2-difluoro Method 1: LCMS Rf 3.476 min at 254 nm, ethyl3.476 min at 220 nm, m/e 365 (M + 1). 590 6-fluoro 2,2-difluoro Method1: LCMS Rf 3.326 min at 254 nm, ethyl 3.326 min at 220 nm, m/e 349 (M +1). 592 6-methoxy 3-fluoropropyl Method 1: LCMS Rf 3.170 min at 254 nm,3.176 min at 220 nm, m/e 357 (M + 1). 593 4-chloro 3-fluoropropyl Method1: LCMS Rf 3.400 min at 254 nm, 3.407 min at 220 nm, m/e 361 (M + 1).594 4-methoxy 3-fluoropropyl Method 1: LCMS Rf 3.326 min at 254 nm,3.327 min at 220 nm, m/e 357 (M + 1). 595 5-methoxy- 3-fluoropropylMethod 1: LCMS Rf 3.277 min at 254 nm, 2-methyl 3.277 min at 220 nm, m/e371 (M + 1). 596 7-methoxy 3-fluoropropyl Method 1: LCMS Rf 3.290 min at254 nm, 3.291 min at 220 nm, m/e 357 (M + 1). 597 6-chloro3-fluoropropyl Method 1: LCMS Rf 3.498 min at 254 nm, 3.499 min at 220nm, m/e 361 (M + 1). 598 6-fluoro 3-fluoropropyl Method 1: LCMS Rf 3.329min at 254 nm, 3.330 min at 220 nm, m/e 345 (M + 1). 600 6-methoxy2,2,2- Method 1: LCMS Rf 3.288 min at 254 nm, trifluoroethyl 3.228 minat 220 nm, m/e 379 (M + 1). 601 4-chloro 2,2,2- Method 1: LCMS Rf 3.518min at 254 nm, trifluoroethyl 3.518 min at 220 nm, m/e 383 (M + 1). 6024-methoxy 2,2,2- Method 1: LCMS Rf 3.427 min at 254 nm, trifluoroethyl3.428 min at 220 nm, m/e 379 (M + 1). 603 5-methoxy- 2,2,2- Method 1:LCMS Rf 3.378 min at 254 nm, 2-methyl trifluoroethyl 3.378 min at 220nm, m/e 393 (M + 1). 604 7-methoxy 2,2,2- Method 1: LCMS Rf 3.234 min at254 nm, trifluoroethyl 3.255 min at 220 nm, m/e 379 (M + 1). 6056-chloro 2,2,2- Method 1: LCMS Rf 3.587 min at 254 nm, trifluoroethyl3.587 min at 220 nm, m/e 383 (M + 1).

The following compounds were prepared by following a similar procedureto Example 545:

No. Z′ R₄ Data 606 6-methoxy 2,2-difluoro- Method 1: LCMS Rf 3.190 minat 254 nm, ethyl 3.190 min at 220 nm. 607 4-fluoro 3- Method 1: LCMS Rf3.390 min at 254 nm, 5-methoxy fluoropropyl 3.395 min at 220 nm, m/e 401(M + 1). 6-fluoro 608 4-fluoro 2,2,2- Method 1: LCMS Rf 3.442 min at 254nm, 6-fluoro trifluoroethyl 3.453 min at 220 nm, m/e 429 (M + 1).5-methoxy

EXAMPLE 620N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzylamine

Combine amine (0.2 mmol) in dichloromethane (0.5 mL) and aldehyde (0.4mmol) in dichloromethane (1 mL) and rotate. After 1 h, add sodiumtriacetoxyborohydride (82 mg, 0.8 mmol) as a stock solution in1-methyl-2-pyrrolidinone (1 mL) and rotate. After overnight rotation,dilute the reaction mixture with 1 mL of methanol and directly apply toa 2 g SCX column. After thoroughly washing with methanol, elute thecolumn with 2 M ammonia-methanol and concentrate the eluent to aresidue, which was further purified by Gilson UV prep system. Compoundwas characterized using method 3. LCMS R_(f) 4.823 min at 254 nm, 4.823min at 220 nm, m/e 443 (M+1).

LC Method:

Method 3: (Shimadzu QP8000) 5-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared using a similar procedure as inExample 620:

No. R⁴ Data 622 2,2,3,3-tetrafluoropropyl Method 3: LCMS Rf 4.681 min at254 nm, 4.692 min at 220 nm, m/e 425 (M + 1). 623 2,2,2-trifluoroethylMethod 3: LCMS Rf 4.639 min at 254 nm, 4.643 min at 220 nm, m/e 393 (M +1).

EXAMPLE 624N-(2-(6-Fluoro-1-methyl-1H-indol-3-yl)ethyl)-N-methyl-3-propoxybenzylamine

Combine N-methyl-N-(2-(6-fluoro-1-methyl-1H-indol-3-yl)ethylamine (0.2mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) and 3-propyloxybenzaldehyde(0.32 mmol) in dichloromethane (1 mL) and rotate. After overnightrotation, add sodium borohydride (1.0 mmol) as a stock solution in1-methyl-2-pyrrolidinone (0.5 mL) and rotate. After rotation for 3 h,dilute the reaction mixture with 1 mL of 10% acetic acid/methanol, anddirectly apply the resulting solution to a 2 g SCX column. Afterthoroughly washing with methanol, elute the column with 2 Mammonia-methanol and concentrate the eluent to a residue, which wasfurther purified by Gilson UV prep system.

LC method:

Method 1: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared following a similar procedure asfound in Example 624:

Z′ R₃ R₄ Data 625 3-trifluoromethyl 4-CH₃ propyl Method 1: LCMS Rf 3.214min 4-fluoro at 254 nm, 3.213 min at 220 nm, m/e 371 (M + 1). 6263-trifluoromethyl H 3,3,3- Method 1: LCMS Rf 3.042 min 4-fluorotrifluoropropyl at 254 nm, 3.042 min at 220 nm, m/e 410 (M + 1). 6273-trifluoromethyl H 2,2-difluoro Method 1: LCMS Rf 2.828 min 4-fluoroethyl at 254 nm, 2.828 min at 220 nm, m/e 378 (M + 1). 6283-trifluoromethyl H 2,2,3,3,3penta method 1: LCMS Rf 3.196 min 4-fluorofluoro at 254 nm, 3.196 min at 220 nm, propyl m/e 446 (M + 1). 6293-trifluoromethyl H 2,2,2- Method 1: LCMS Rf 2.984 min 4-fluorotrifluoroethyl at 254 nm, 2.984 min at 220 nm, m/e 396 (M + 1). 6303-trifluoromethyl H 3-fluoro Method 1: LCMS Rf 2.855 min 4-fluoro propylat 254 nm, 2.855 min at 220 nm, m/e 374 (M + 1).

No. Z′ R₃ R₄ Data 632 5-fluoro 4- propyl Method 1: LCMS Rf 3.141 min at254 6-chloro methyl nm, 3.140 mm at 220 nm, m/e 375 (M + 1). 633 6- H3,3,3-trifluoro Method 1: LCMS Rf 3.065 min at 254 trifluoro propyl nm,3.066 min at 220 nm, m/e 431 methyl (M + 1). 634 5-fluoro H3,3,3-trifluoro Method 1: LCMS Rf 2.977 min at 254 6-chloro propyl nm,2.977 min at 220 nm, m/e 415 (M + 1). 635 5,6- H 3,3,3-trifluoro Method1: LCMS Rf 2.871 min at 254 difluoro propyl nm, 2.872 min at 220 nm, m/e399 (M + 1). 636 6- H 3,3,3-trifluoro Method 1: LCMS Rf 3.065 min at 254trifluoro propyl nm, 3.066 min at 220 nm, m/e 431 methyl (M + 1). 6375-fluoro H 2,2-difluoro Method 1: LCMS Rf 2.782 min at 254 6-chloroethyl nm, 2.782 min at 220 nm, m/e 383 (M + 1). 638 5,6- H 2,2-difluoroMethod 1: LCMS Rf 2.655 min at 254 difluoro ethyl nm, 2.655 min at 220nm, m/e 367 (M + 1). 639 6- H 2,2-difluoro Method 1: LCMS Rf 2.876 minat 254 trifluoro ethyl nm, 2.875 min at 220 nm, m/e 399 (M + 1). methyl640 6- H 2,2,2 trifluoro Method 1: LCMS Rf 3.009 min at 254 trifluoroethyl nm, 3.009 min at 220 nm, m/e 417 (M + 1). methyl 641 5-fluoro H2,2,3,3,3- Method 1: LCMS Rf 3.135 min at 254 6-chloro pentafluoro nm,3.135 min at 220 nm, m/e 451 (M + 1). propyl 642 5,6- H 2,2,3,3,3-Method 1: LCMS Rf 3.027 min at 254 difluoro pentafluoro nm, 3.027 min at220 nm, m/e 435 (M + 1). propyl 643 6- H 2,2,3,3,3- Method 1: LCMS Rf3.202 min at 254 trifluoro pentafluoro nm, 3.202 min at 220 nm, m/e 467(M + 1). methyl propyl 645 5,6- H 2,2,2-trifluoro Method 1: LCMS Rf2.982 min at 254 difluoro ethyl nm, 2.982 min at 220 nm, m/e 396 (M + 1)646 6- H 2,2,2- Method 1: LCMS Rf 3.009 min at 254 trifluorotrifluoroethyl nm, 3.009 min at 220 nm, m/e 417 (M + 1). methyl 6475-fluoro H 3-fluoro Method 1: LCMS Rf 2.796 min at 254 6-chloro propylnm, 2.796 min at 220 nm, m/e 379 (M + 1). 648 5,6- H 3-fluoro Method 1:LCMS Rf 2.644 m/e at 254 difluoro propyl nm, 2.646 min at 220 nm, m/e363 (M + 1). 649A 6- H 3-fluoro Method 1: LCMS Rf 2.900 min at 254trifluoro propyl nm, 2.900 min at 220 nm, m/e 395 (M + 1). methyl

No. Z′ R₃ R₄ Data 631 6-fluoro 4-methyl propyl Method 1: LCMS Rf 3.152min at 220 nm, m/e 355 (M + 1). 633A 6-fluoro H 3,3,3- Method 1: LCMS Rf2.949 min at 254 trifluoro nm, 2.953 min at 220 nm, m/e 395 propyl (M +1). 640A 6-fluoro H 2,2,3,3,3- Method 1: LCMS Rf 3.112 min at 254pentafluoro nm, 3.117 min at 220 nm, m/e 431 propyl (M + 1). 6496-fluoro H 2,2,2- Method 1: LCMS Rf 2.895 min at 254 trifluoro nm, 2.898min at 220 nm, m/e 381 ethyl (M + 1).

EXAMPLE 650 N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine

Combine 2-(3-chlorophenyl)ethylamine (1.866 gm; 15.28 mmol) and3-hydroxybenzaldehyde (1.567 gm; 10.07 mmol) in 40 mL of methanol andstir at room temperature for 20 min and treat with sodium borohydride(0.950 gm; 25.1 mmol) in one portion. Stir the mixture at roomtemperature. After 15 h, add water (10 mL), and remove the methanol byrotary evaporation. Add to this slurry water (25 mL) and dichloromethane(50 mL), separate the layers and extract the aqueous layer withdichloromethane (50 mL). Wash the combined organic layers with saturatedbrine (3×), dry over MgSO₄, and concentrate to give the title compound.

EXAMPLE 650AN-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine

Combine N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine, dichloromethane(40 mL), and di-tert-butyl dicarbonate (1.556 gm; 7.131 mmol) andtriethylamine (1.0 mL; 7.2 mmol). After 18 hours, pour into water (50mL), separate the layers, and extract the aqueous layer withdichloromethane. Wash combined organic layers with water, dry overMgSO₄, and concentrate. Chromatograph on silica gel eluting with 5%ethyl acetate in hexanes to give the title compound.

EXAMPLE 651N-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine

Add a solution of 50% sodium hydroxide in water (0.8 mL) to a solutionof N-t-butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-hydroxybenzylamine(46.7 mg, 0.129 mmol), n-propyl iodide (0.17 gm. 1.00 mmol), andtetrabutylammonium bromide (18 mg, 0.057 mmol) in toluene (1 mL). Stirthe mixture at 1200 rpm and heat at 50-54° C. After 64.5 hour pour themixture into 5 mL of water, separate the phases and extract the aqueousphase twice with dichloromethane. Combine the organic phases and washwith saturated sodium bicarbonate solution, and then saturated brine,dry (MgSO₄), and concentrate to give a residue. Chromatograph theresidue on silica gel to give the title compound: MS (ES+): m/e (M+1)404. TLC (20% EtOAc in hexanes, R_(f) 0.54).

EXAMPLE 652 N-(2-(3-Chlorophenyl)ethyl)-3-propoxybenzylamine

Add methanesulfonic acid (70 uL) to a solution ofN-t-Butoxycarbonyl-N-2-(3-chlorophenyl)ethyl-3-propoxybenzylamine indichloromethane (4 mL) and agitate the mixture for 3 hours at roomtemperature. Add 10% aqueous Na₂CO₃ (2 mL), separate the layers, andconcentrate the organic layer in a nitrogen stream to give a residue.Dissolve the residue in 4 mL of 5% acetic acid in methanol and passthrough a 1 gm SCX column, eluting with 1 M ammonia in methanol to givethe title compound: MS (ES+): m/e (M+1). HPLC (10-90% water/acetonitrileover 7.5 min, Tr=4.490 min).

The following compounds were prepared by a similar procedure to Examples651 and 652:

No. R₄ Data 654 ethyl Method 1: LCMS Rf 4.223 min at 254/220 nm; m/e298.9 (M + 1) 655 butyl Method 1: LCMS Rf 4.715 min at 254/220 nm; m/e317.9 (M + 1) 656 hexyl Method 1: LCMS Rf 5.137 min at 254/220 nm; m/e345.9 (M + 1) 658 allyl Method 1: LCMS Rf 4.373 min at 254/220 nm; m/e301.9 (M + 1) 660 pyridin-2- Method 1: LCMS Rf 3.547 min at 254/220 nm;m/e ylmethyl 352.9 (M + 1) 661 pyridin-3- Method 1: LCMS Rf 3.487 min at254/220 nm; m/e ylmethyl 352.9 (M + 1) 662 pyridin-4- Method 1: LCMS Rf3.455 min at 254/220 nm; m/e ylmethyl 352.9 (M + 1)

EXAMPLE 665 N-(2-(5-Methoxy-1-ethyl-1H-indol-3-ylethyl-N-ethyl-3-phenyoxybenzylamine

Add acetaldehyde (0.080 mL; 0.77 mmol) to a solution ofN-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-phenyoxybenzylamine (free base,55.5 mg, 0.149 mmol) in dichloromethane (1 mL) followed by a suspensionof sodium triacetoxyborobydride (64 mg; 0.30 mmol) in dichloromethane (1mL). After 44 hours, quench by the addition of methanol (0.5 mL) andconcentrate in a stream of nitrogen to give a residue. Dissolve theresidue in 4 mL of 5% acetic acid in methanol and partially purify bypassage through a 1 gm SCX column, eluting with 1 M ammonia in methanolto give a residue. Chromatograph the residue by preparative HPLC (C-18column, flow rate of 20 ml/min, 5-90% water/acetonitrile over 12 min) togive the title compound: MS (ES+): m/e (+1); HPLC: (10-90%water/acetonitrile over 10 min, Tr=5.25 min).

The following compounds were prepared following a similar procedure inExample 665:

No. R₂ Data 666 methyl LC Method 2: Rf 5.12 min at 254/220 nm; m/e 351.9(M + 1) 667 ethyl LC Method 2: Rf 5.25 min at 254/220 nm; m/e 365.9 (M +1)

No. R₂ Data 668 ethyl LC Method 2: Rf 4.98 min at 254/220 nm; m/e 401.09(M + 1)

EXAMPLE 670 3-Propoxybenzaldehyde

Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide(17.3 gm; 102 mmol), and potassium carbonate (16.90 gm; 122 mmol) in2-butanone (100 mL) and reflux. After 17 h, allow the mixture to cool toroom temperature, decant the solution and concentrate by rotaryevaporation. Partition the residue between diethyl ether (150 mL) andwater (150 mL), separate the layers and extract the aqueous layer withdiethyl ether (2×100 mL). Combine organic layers and wash with water, 1N NaOH, and then water, dry over MgSO₄, and concentrate to give aresidue. Distill the residue to give the title compound: bp: 122-125° C.(15 mm); TLC (10% Et₂O/hexanes; R_(f) 0.35).

EXAMPLE 671 3-(3,3,3-Trifluoropropoxy)benzaldehyde

Cool a mixture of toluenesulfonyl chloride (7.43 gm; 39.0 mmol) andpyridine (50 mL) to 0° C., add 3,3,3-3,3,3-trifluoropropanol (2.23 gm;19.5 mmol) and store the mixture at 3° C. After 48 hour pour thereaction mixture into 350 mL of ice water and extract with diethyl ether(3×125 mL). Combine the organic layers and wash with 5 N HCl, water,saturated sodium bicarbonate solution, and brine, dry over MgSO₄, andconcentrate to give 3,3,3-trifluoropropyl tosylate. The material wascarried into the next step without purification.

Combine 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12 mmol),3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol), and K₂CO₃ (4.15 gm; 30.0mmol) in DMF (80 mL) and heat at 100° C. After 18 hours, cool to roomtemperature, dilute with water (200 mL) and extract with dichloromethane(2×200 mL). Combine organic extracts and wash sequentially with water(100 mL), 0.1 M NaOH (2×100 mL), saturated sodium bicarbonate (100 mL)and saturated brine (100 mL), dry (MgSO₄), and concentrate.Chromatography on silica gel (0-20% ethyl acetate in hexane) to give thetitle product.

EXAMPLE 672 3-(2-Fluoroethoxy)benzaldehyde

Combine 1-bromo-2-fluoroethane (4.575 g; 36.0 mmol),3-hydroxybenzaldehyde (4.103 gm; 33.60 mmol), and K₂CO₃ (7.05 gm; 51.0mmol) in 2-butanone (100 mL) and reflux. After 18 hour cool the mixtureto ambient temperature, concentrate, and partition between 100 mL ofwater and 100 mL of dichloromethane. Separate the layers and extract theaqueous layer with dichloromethane (2×75 mL). Combine the organic layersand wash sequentially with brine (2×150 mL), 1 M NaOH (2×100 mL), NaHCO₃(saturated, 100 mL), and brine (150 mL), dried (MgSO₄), concentrate, andchromatograph on silica gel (0-25% diethyl ether in hexanes) to give thetitle compound.

EXAMPLE 673 N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-3-propoxybenzylamine

Combine 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL). Add asolution of sodium borohydride in diglyme (1 ml of a 0.5 M solution;0.50 mmol) and agitate. After 63 h at room temperature concentrate in astream of nitrogen. Dissolve the residue in methanol and add to a 1 gmSCX column previously rinsed with 5% acetic acid in methanol. Elute theproduct from the SCX column with 1 M ammonia in methanol to give thetitle compound: MS (ES+): m/e (M+1); HPLC (10-90% water/acetonitrileover 10 min, Tr=4.08 min.

General LC Methods:

Method 1: (Shimadzu Class VP HPLC and Micromass Platform LC with HP1100LC system) 10-90 in 7.5 min. Solvent A: water 0.1% trifluoroacetic acid,Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 Metachem,monochrom 3 micron, 2.5×2.5.

Method 2: (Shimadzu Class VP HPLC and Micromass Platform LC with HP1100LC system) 10-90 in 10 min. Solvent A: water 0.1% trifluoroacetic acid,Solvent B: acetonitrile 0.1% trifluoroacetic acid. Column: C18 Metachem,monochrom 3 micron, 2.5×2.5.

Method 3: (Waters Millennium HPLC and Micromass Platform LC with HP1100LC system) 10-100 in 10 min. Solvent A: 0.1% trifluoroacetic acid,Solvent B: acetonitrile 0.08% trifluoroacetic acid. Column: YMC, 5micron, 2.5×25.

Method 4: (Shimadzu QP8000) 10-90 in 4.5 min. Solvent A: water 0.1%trifluoroacetic acid, Solvent B: acetonitrile 0.1% trifluoroacetic acid.Column: C18 Metachem, monochrom 3 micron, 2.5×25.

The following compounds were prepared following a procedure followingExample 673:

No. Z′ Data 675 2-fluoro LC Method 3: Rf 4.18 min at 254/220 nm; m/e322.0 (M + 1) 676 3-fluoro LC Method 3: Rf 4.23 min at 254/220 nm; m/e322.0 (M + 1) 677 4-chloro LC Method 3: Rf 4.48 min at 254/220 nm; m/e337.9 (M + 1) 678 4-hydroxy LC Method 3: Rf 3.62 min at 254/220 nm; m/e320.0 (M + 1) 679 2-methoxy LC Method 3: Rf 4.30 min at 254/220 nm; m/e334.0 (M + 1) 680 4-bromo 3-methoxy LC Method 3: Rf 4.50 min at 254/220nm; m/e 411.9 (M + 1) 681 4-fluoro LC Method 3: Rf 4.22 min at 254/220nm; m/e 322.0 (M + 1) 682 2-chloro LC Method 3: Rf 4.36 min at 254/220nm; m/e 338.0 (M + 1) 683 4-bromo LC Method 3: Rf 4.55 min at 254/220nm; m/e 383.91 (M + 1) 684 4-methyl LC Method 3: Rf 4.42 min at 254/220nm; m/e 318.0 (M + 1) 685 3-methoxy LC Method 3: Rf 4.19 min at 254/220nm; m/e 334.0 (M + 1) 686 4-methoxy LC Method 3: Rf 4.15 min at 254/220nm; m/e 334.0 (M + 1) 687 2-ethoxy LC Method 3: Rf 4.55 min at 254/220nm; m/e 348.0 (M + 1) 688 4-ethoxy LC Method 3: Rf 4.43 min at 254/220nm; m/e 348.0 (M + 1) 689 4-phenoxy LC Method 3: Rf 5.00 min at 254/220nm; m/e 396.0 (M + 1) 690 4-sulfonamide LC Method 3: Rf 3.46 min at254/220 nm; m/e 383.0 (M + 1) 691 3,4-dichloro LC Method 3: Rf 4.74 minat 254/220 nm; m/e 372.0 (M + 1) 692 2,5-dichloro LC Method 3: Rf 4.74min at 254/220 nm; m/e 372.0 (M + 1) 693 2,6-dichloro LC Method 3: Rf4.51 min at 254/220 nm; m/e 372.0 (M + 1) 694 2,5-dimethoxy LC Method 3:Rf 4.31 min at 254/220 nm; m/e 364.0 (M + 1) 695 2,3-dimethoxy LC Method3: Rf 4.24 min at 254/220 nm; m/e 364.0 (M + 1) 696 3,5-dimethoxy LCMethod 3: Rf 4.26 min at 254/220 nm; m/e 364.0 (M + 1) 6973-ethoxy-4-methoxy LC Method 3: Rf 4.14 min at 254/220 nm; m/e 378.0(M + 1)

The following compounds were prepared following a procedure followingExample 673:

No. Z′ Data 698 5-methyl LC Method 4: Rf 2.852 min at 254/220 nm; m/e357 (M + 1) 699 5-chloro LC Method 4: Rf 2.893 min at 254/220 nm; m/e377 (M + 1)

No. Z′ Data 700 2-fluoro LC Method 3: Rf 3.90 min at 254/220 nm; m/e288.0 (M + 1) 701 3-fluoro LC Method 3: Rf 3.95 min at 254/220 nm; m/e288.0 (M + 1) 702 4-fluoro LC Method 3: Rf 3.96 min at 254/220 nm; m/e288.0 (M + 1) 703 2-chloro LC Method 3: Rf 4.23 min at 254/220 nm; m/e303.9 (M + 1) 704 4-chloro LC Method 3: Rf 4.12 min at 254/220 nm; m/e303.9 (M + 1) 705 4-bromo LC Method 3: Rf 4.33 min at 254/220 nm; m/e347.9 (M + 1) 706 4-methyl LC Method 3: Rf 4.17 min at 254/220 nm; m/e284.0 (M + 1) 707 4-hydroxy LC Method 3: Rf 3.26 min at 254/220 nm; m/e286.0 (M + 1) 708 2-methoxy LC Method 3: Rf 4.03 min at 254/220 nm; m/e300.0 (M + 1) 709 3-methoxy LC Method 3: Rf 3.91 min at 254/220 nm; m/e300.0 (M + 1) 710 4-methoxy LC Method 3: Rf 3.91 min at 254/220 nm; m/e300.0 (M + 1) 711 3-ethoxy LC Method 3: Rf 4.31 min at 254/220 nm; m/e314.0 (M + 1) 712 4-ethoxy LC Method 3: Rf 4.14 min at 254/220 nm; m/e314.0 (M + 1) 713 4-phenoxy LC Method 3: Rf 4.77 min at 254/220 nm; m/e362.0 (M + 1) 714 4-sulfonamide LC Method 3: Rf 3.06 min at 254/220 nm;m/e 349.0 (M + 1) 715 3,4-dichloro LC Method 3: Rf 4.52 min at 254/220nm; m/e 337.9 (M + 1) 716 2,5-dichloro LC Method 3: Rf 4.51 min at254/220 nm; m/e 337.9 (M + 1) 717 2,6-dichloro LC Method 3: Rf 4.28 minat 254/220 nm; m/e 337.9 (M + 1) 718 3,4-dimethoxy LC Method 3: Rf 3.59min at 254/220 nm; m/e 330.0 (M + 1) 719 2,5-dimethoxy LC Method 3: Rf4.04 min at 254/220 nm; m/e 330.0 (M + 1) 720 2,3-dimethoxy LC Method 3:Rf 3.96 min at 254/220 nm; m/e 330.0 (M + 1) 721 3,5-dimethoxy LC Method3: Rf 3.99 min at 254/220 nm; m/e 330.0 (M + 1) 722 3-bromo 4-methoxy LCMethod 3: Rf 4.22 min at 254/220 nm; m/e 379.9 (M + 1) 7234-ethoxy-3-methoxy LC Method 3: Rf 3.88 min at 254/220 nm; m/e 344.0(M + 1) 724 3-ethoxy-4-methoxy LC Method 3: Rf 3.84 min at 254/220 nm;m/e 344.0 (M + 1)

The following compounds were prepared following a procedure followingExample 673:

No. R₁ Data 725 pyridine-2-yl LC Method 3: Rf 2.38 min at 254/220 nm;m/e 271.0 (M + 1) 726 pyridin-3-yl LC Method 3: Rf 2.25 min at 254/220nm; m/e 271.0 (M + 1) 727 pyridin-4-yl LC Method 3: Rf 2.21 min at254/220 nm; m/e 271.0 (M + 1) 729 7-methyl-1H-indol-3-yl LC Method 3: Rf4.19 min at 254/220 nm; m/e 323.0 (M + 1) 730 6-methoxy-1H-indol-3-yl LCMethod 3: Rf 3.90 min at 254/220 nm; m/e 339.0 (M + 1) 731 thiophen-3-ylLC Method 3: Rf 3.70 min at 254/220 nm; m/e 275.9 (M + 1) 7325-methyl-1H-indol-3-yl LC Method 4: Rf 2.680 min at 254/220 nm; m/e 323(M + 1) 733 5-chloro-1H-indol-3-yl LC Method 4: Rf 4.019 min at 254/220nm; m/e 344 (M + 1)

The following compounds were prepared following a procedure followingExample 673:

No. Z′ R₄ Data 734 5-methyl 2-fluoroethyl LC Method 4: Rf 2.381 min at254/220 nm; m/e 327 (M + 1) 735 5-fluoro 2-fluoroethyl LC Method 4: Rf2.300 min at 254/220 nm; m/e 331 (M + 1) 736 5-methyl 2,2-difluoroethylLC Method 4: Rf 2.520 min at 254/220 nm; m/e 345 (M + 1) 737 5-fluoro2,2difluoroethyl LC Method 4: Rf 2.445 min at 254/220 nm; m/e 349(M + 1) 738 5-chloro 2,2-difluoroethyl LC Method 4: Rf 2.598 min at254/220 nm; m/e 365 (M + 1) 739 5-fluoro 4,4,4-trifluorobutyl LC Method4: Rf 3.017 min at 254/220 nm; m/e 395 (M + 1) 740 5-fluoro2,2,2-trifluoroethyl LC Method 4: Rf 2.787 min at 254/220 nm; m/e 367(M + 1) 741 5-methoxy 2,2,2-trifluoroethyl LC Method 4: Rf 2.681 min at254/220 nm; m/e 379 (M + 1) 742 5-chloro 4,4,4-trifluorobutyl LC Method4: Rf 3.151 min at 254/220 nm; m/e 411 (M + 1) 743 5-fluoro3-fluoropropyl LC Method 4: Rf 2.475 min at 254/220 nm; m/e 345 (M + 1)744 5-methoxy 3,3,3-trifluoropropyl LC Method 4: Rf 2.889 min at 254/220nm; m/e 393 (M + 1) 745 5-chloro 3-fluoropropyl LC Method 4: Rf 2.628min at 254/220 nm; m/e 361 (M + ) 746 5-fluoro 2,2,3,3- LC Method 4: Rf2.680 min at tetrafluoropropyl 254/220 nm; m/e 399 (M + 1) 747 5-methyl2,2,3,3- LC Method 4: Rf 2.756 min at tetrafluoropropyl 254/220 nm; m/e397 (M + 1) 748 5-chloro 2,2,3,3- LC Method 4: Rf 2.820 min attetrafluoropropyl 254/220 nm; m/e 417 (M + 1) 750 5-fluoro 2,2,3,3,3- LCMethod 4: Rf 2.833 min at pentafluoropropyl 254/220 nm; m/e 417 (M + 1)751 5-methyl 2,2,3,3,3- LC Method 4: Rf 2.908 min at pentafluoropropyl254/220 nm; m/e 415 (M + 1) 752 5-chloro 2,2,3,3,3- LC Method 4: Rf2.784 min at pentafluoropropyl 254/220 nm; m/e 433 (M + 1) 754 5-methyl3-fluoropropyl LC Method 4: Rf 2.457 min at 254/220 nm; m/e 341 (M + 1)755 5-methoxy 4,4,4-trifluorobutyl LC Method 4: Rf 2.931 min at 254/220nm; m/e 406 (M + 1) 756 5-methoxy 2,2,3,3- LC Method 4: Rf 2.795 min attetrafluoropropyl 254/220 nm; m/e 411 (M + 1) 757 5-chloro 2-fluoroethylLC Method 4: Rf 2.477 min at 254/220 nm; m/e 347 (M + 1)

The following compounds were prepared following a procedure followingExample 673:

No. Z′ R₄ Data 758 3-trifluoro 2,2,3,3- LC Method 4: Rf 2.650 min atmethyl tetrafluoro propyl 254/220 nm; m/e 410 (M + 1) 759 3-trifluoro4,4,4-trifluoro LC Method 4: Rf 2.761 min at methyl butyl 254/220 nm;m/e 406 (M + 1)

EXAMPLE 760 3-Trifluoromethoxyphenethylamine

Combine nitromethane (1.8 g, 30 mmol), ethanol (4 mL) and 10 N NaOH (0.1mL). Add 3-trifluoromethoxybenzaldehyde (5.0 g, 28.6 mmol) and stir.After 20 hours, pour into ethyl acetate, wash with water, dried overNa₂SO₄, filter, and concentrate to give a residue. Chromatograph theresidue on silica gel to give2-nitro-1-(3-trifluoroethoxyphenyl)ethanol: MS (M−1) 250; ¹H NMR (CDCl₃)7.45 (1H, t, J=8.4 Hz), 7.36-7.30 (2 h, m), 7.24-7.20 (1 h, m), 5.51 (1h, dt, J=8.8 and 4.0 Hz), 4.62-4.51 (2H, m).

Combine 2-nitro-1-(3-trifluoroethoxyphenyl)ethanol (6.1 g, 24.2 mmol)and methanesulfonyl chloride (2.02 mL) in dichloromethane (50 mL) andcool in an ice-bath. Add dropwise, triethylamine (7.28 mL) whilemaintaining the temperature near 0° C. After 2 hours, pour into ethylacetate, wash with water, dry with Na₂SO₄, filter, and then concentrateto residue. Chromatograph the residue on silica gel to give3-(2-nitrovinyl)-1-trifluoroethoxybenzene: MS (MH⁺) 234; ¹H NMR (CDCl₃)7.97 (1H, d, J=13.6 Hz), 7.57 (1H, d, J=13.6 Hz), 7.53-7.48 (2H, m),7.40-7.35 (2H, m).

Combine 3-(2-nitrovinyl)-1-trifluoroethoxybenzene (3.0 g, 12.88 mmol)and methanol (50 mL) and concentrated HCl (5 mL) and hydrogenate atambient temperature and 50 psi (340 kPa) in the presence of PtO₂ (0.6g). After 5 hours, filter to the catalyst, dilute the filtrate with 1NHCl (50 mL) and wash with ethyl acetate. Separate the aqueous layer,neutralize with 2N NaOH (100 mL), extract with ether, dry with Na₂SO₄,filter and then concentrated to give the title compound which can beused without further purification. MS (MH⁺) 206; ¹H NMR (CDCl₃) 7.32(1H, t, J=7.6 Hz), 7.18-7.06 (3H, m), 2.98 (2H, t, J=7.2 Hz), 2.77 (2H,t, J=7.2 Hz).

EXAMPLE 761N-(2-(3-Trifluoromethoxyphenyl)ethyl)-3-(2,2,2-trifluoroethyl)benzylamine

Combine trifluoromethoxyphenethylamine (400 mg, 1.95 mmol), and3-(2-trifluoroethoxy)benzaldehyde (596 mg, 2.92 mmol), and 4 Å molecularsieve (4.0 g) in ethanol (30 mL) and reflux. after 4.5 hours, decant andtreat of NaBH₄ (221 mg, 5.85 mmol). After 1 hour, evaporate andpartition between 5N NaOH and dichloromethane. Separate the organiclayer, dry over Na₂SO₄, filter, and concentrate to give a residue.Chromatograph the residue by HPLC to give the title compound. The HClsalt of the title compound gives a white solid: MS (MH⁺) 394; ¹H(DMSO-d₆) 9.48 (2H, br s), 7.48 (I H, t, J=7.6 Hz), 7.40 (1H, t, J=8.0Hz), 7.34 (1H, s), 7.32-7.21 (4H, m), 7.11 (1H, dd, J=8.4 and 2.8 Hz),4.79 (2H, q, J=8.8 Hz), 4.15 (2H, s), 3.22-3.12 (2H, m), 3.11-3.04 (2H,m).

EXAMPLE 762N-(2-(3-Trifluoromethoxyphenyl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylamine

The method of Example 761 gives the title compound. The HCl salt of thetitle compound gives a white solid: MS (MH⁺) 426; ¹H (DMSO-d6) 9.42 (2H,br s), 7.48 (1H, t, J=7.6 Hz), 7.40 (1H, t, J=7.6 Hz), 7.32-7.26 (3H,m), 7.20 (1H, d, J=7.2 Hz), 7.11 (1H, dd, J=8.4 and 2.8 Hz), 6.70 (1H,tt, J=52 and 5.2 Hz), 4.62 (2H, t, J=13.6 Hz), 4.15 (2H, s), 3.22-3.12(2H, m), 3.10-3.02 (2H, M).

EXAMPLE 763N-(2-(4,7-Difluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

Combine 2-(4,7-difluoro-1H-indol-3-yl)ethylamine (483 mg, 2.46 mmol) andethanol (45 mL) and stir. After 10 minutes treat with3-(2,2,2-trifluoroethoxy)benzaldehyde (502 mg, 2.46 mmol) and anhydroussodium sulfate (3.5 g) and stir under nitrogen and heat at 70° C. After2 h, cool the reaction vacuum filter to remove the sodium sulfate andtreat with sodium borohydride (279 mg, 7.38 mmol) in a 500 mL roundbottom flask equipped with magnetic stirring. Allow the solution to stirfor 2 hours at room temperature and then carefully treat with threedrops of glacial acetic acid to quench the excess hydride. Remove thesolvent in vacuo and re-dissolve the crude material in methanol. Purifyby a 10 g SCX column by washing thoroughly with methanol, eluting with2N ammonia in methanol, and concentrating in vacuo to give the titlecompound as a straw colored oil. Prepare the hydrochloride salt bydissolving the free base (800 mg, 2.08 mmol) in methanol (15 mL) andtreating with a solution of ammonium chloride (111 mg, 2.08 mmol) inmethanol (5 mL). Sonicate the mixture for 10 minutes beforeconcentrating in vacuo to give a white solid. Recrystallize from ethylacetate to obtain the hydrochloride salt of the title compound: mp208.5-210.0° C.; ¹H NMR (400 MHz, dmso-d6): 11.79 (br s, 1H), 9.21 (brs, 2H), 7.39 (t, 1H, J=7.8 Hz), 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H),7.18 (d, 1H, J=8.0 Hz), 7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85-6.91 (m, 1H),6.67-6.73 (m, 1H), 4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12-3.16 (m,4H); MS (APCI): in/e 385.1 (M+1); CHN (for C₁₉H₁₇F₅NO.HCl) calcd: C,54.23; H, 4.31; N, 6.66; found: C, 54.20; H, 4.30; N, 6.66.

EXAMPLE 764N-(2-(4,5,6,7-Tetrafluoro-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine

By a method similar to Example 763, using2-(4,5,6,7-tetrafluoro-1H-indol-3-yl)ethylamine (484 mg, 2.08 mmol),ethanol (45 mL), 3-(2,2,2-trifluoroethoxy)benzaldehyde (425 mg, 2.08mmol), anhydrous sodium sulfate (3.5 g) sodium borohydride (236 mg, 6.24mmol) to give the free base of the title compound as a straw coloredsolid. Recrystallize from methylene chloride to obtain the titlecompound: mp 107.2-108.2° C. ¹H NMR (400 MHz, dmso-d6): 11.92 (br s,1H), 7.32 (s, 2H), 6.95-6.99 (m, 2H), 6.87 (dd, 1H, J=2.4, 8.0 Hz) 4.68(q, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t, 2H,J=7.2 Hz). MS (ES+): m/e 421.1 (M+1). CHN (for C₁₉H₁₅F₇N₂O.HCl.0.20H₂O)calcd: C, 53.83; H, 3.66; N, 6.61; found: C, 53.75; H, 3.33; N, 6.

EXAMPLE 765 5-Trifluoromethyltryptamine

Combine 4-trifluoromethylaniline (32.2 g, 199.8 mmol) anddichloromethane (600 ml) in a 2 L round bottomed flask under nitrogenand cool to −70° C. Add tert-butylhypochlorite (protected from thelight) (22.8 g, 210 mmol) in dichloromethane (150 ml) stir for a totalof 45 min at about −65 to −70° C. At 35 min, add a solution ofmethylthioacetaldehyde dimethylacetal (30 g, 220.2 mmol) indichloromethane (150 ml) is added. At 45 min at −70° C., add a solutionof triethylamine (31.2 ml, 22.78 g, 225.1 mmol) in dichloromethane (80ml). Bring the reaction mixture to room temperature. Wash with water andevaporate to dryness to give 72 g an oil.

Dissolve the oil in toluene (600 ml) and add triethylamine (60 ml). Heatto reflux. After 24 hours, evaporate the solvent and dry the residueunder vacuum to yield 7a residue. Combine the residue, diethyl ether(600 ml), and 2N HCl (500 ml) and stir 24 hours at room temperature.Separate the aqueous layer and wash the organic layer successively withwater and saturated NaHCO₃, dry over MgSO₄, filter, and evaporate togive a residue. Chromatograph on silica gel by eluting withcyclohexane-ethyl acetate (8/2, v/v), and pool the fractions containingthe expected and evaporate to give 33.8 g of2-methylthio-5-trifluoromethyl-1H-indole.

Combine moist Raney nickel (330 g),2-methylthio-5-trifluoromethyl-1H-indole (33.8 g, 146.2 mmol) andabsolute ethanol (850 ml) and stir. After 1.5 hours, filter the mixturethrough celite and wash the celite with ethanol (500 ml). Evaporate thefiltrate to dryness, add toluene (20 ml) and evaporate and dry to give5-trifluoromethylindole: mp=55-60° C.

Dissolve 5-trifluoromethylindole (24 g, 130 mmol) in anhydrous diethylether (288 ml) and cool to 10° C. and add dropwise oxalyl chloride (12ml) over 10 min. (exothermic reaction) and stir at room temperature for4 h. Add and additional amount of oxalyl chloride (3 ml) and stirovernight at room temperature to give a solid. Collect the solid, washwith anhydrous diethyl ether (20 ml), and dry to give2-(5-(trifluoromethyl-1H-indol-3-yl)-2-oxo-acetyl chloride.

Combine 2-(5-(trifluoromethyl-1H-indol-3-yl)-2-oxo-acetyl chloride anNH₄OH 1N (700 ml) and stir the suspension intensely. After 3 hours,collect the 2-(5-(trifluoromethyl)-1H-indol-3-yl)-2-oxo-acetamide.

Add LiAlH₄ (37.95 g, 1.00 mol) to THF (650 mL) under ice-bath cooling.Prepare a solution of AlCl₃ (50 g, 375 mmol) in THF (600 ml) and adddropwise to the LiAlH₄ solution over 45 min at 5-10° C. Whilemaintaining the temperature at about 5° C., add a solution of2-(5-(trifluoromethyl)-1H-indol-3-yl)-2-oxo-acetamide (21.4 g, 83.5mmol) in THF (600 ml) and stir overnight with warming to ambienttemperature. Cool the mixture with ice water and treat with 30% NaOH(100 ml) while maintaining the temperature at less than about 30° C.After stirring for about 30 minutes, filter, wash with THF (2 L), andevaporate the filtrate to give the title compound. Form of the HCl saltby dissolving the title compound in diethyl ether and adding of asolution of HCl in diethyl ether (until acidic). Collect the solid byfiltration, wash with diethyl ether, and dry under reduced pressure togive the hydrochloride salt of the title compound.

The title compound can be further purified by basic extraction of thehydrochloride salt into ethyl acetate, drying over MgSO₄, filter, andevaporate to dryness followed by hydrochloride salt formation in diethylether.

EXAMPLE 766 3-Propoxybenzaldehyde

Combine 3-hydroxybenzaldehyde (790 g), K₂CO₃, (1627 g) and DMF (8 L).Add 1-iodopropane (1000 g) and heat to 105° C. and stir for 4 h. Cool toabout 50° C. and add water (15 L), continue cooling to about roomtemperature and add toluene (10 L). Separate the organic layer andextract the aqueous phase with toluene (2×10 L), combine organic phasesand wash with NaOH 1N (2×5.8 L), concentrate the combined organic layersin vacuo to afford the title compound.

EXAMPLE 777 N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-propoxybenzylamine

Combine 3-propoxybenzaldehyde (14.05 g, 0.0856 mole) and5-methoxytryptamine (13.64 g, 0.0717 mole) in 390 mL absolute EtOH. Addmolecular sieves (19.2 g) and heat the suspension to reflux. After 4hours, cool to room temperature and add NaBH₄ (37.32 g, 0.2146 mole) in3 portions. Stir the mixture for 1 hour at room temperature, filter,evaporate the filtrate to a mass of about 100 g, add water anddichloromethane. After separation, wash the aqueous phase withdichloromethane, combine the organic layers, dry over MgSO₄, filter,evaporate the solvent in vacuo to afford the title compound.

Combine the title compound and isopropanol (250 mL) and slowly add asolution of HCl in EtOH (33 ml, 2.5N). Heat to reflux and stir for 30min. Cool to room temperature and stir for 2 h to give a solid. collectthe solid by filtration, wash isopropanol, and dry to give thehydrochloride salt of the title compound.

EXAMPLE 778 2,2,3,3,3-Pentafluoropropyl tosylate

Combine 2,2,3,3,3-pentafluoropropan-1-ol (9.7 ml) and pyridine. Cool tobetween 0° C. and 10° C. and add portion-wise thep-toluenesulfonylchloride (6.2 g) and stir with warming to roomtemperature. After 3 hours at room temperature, pour the reactionmixture into ice water and stir for 30 min to give a solid. Filter thesolid, wash with water, and dry to give of the title compound.

EXAMPLE 779 3,3,3-Trifluoro-propyl tosylate

Add 3,3,3-trifluoropropan-1-ol (61.8 ml) and pyridine (224 ml). Cool tobetween 0° C. and 10° C. and add portion-wise p-toluenesulfonylchloride(147 g). Allow to warm to ambient temperature and stir overnight. AddHCl 0.5N (1.6 L), extract with ethyl acetate, combine the organiclayers, dry over MgSO₄, filter, and evaporate to give the titlecompound.

EXAMPLE 780 6-Fluorotryptamine

Add dropwise 422 mL of glacial acetic acid to 40% aqueous dimethylamine(408 mL) over 40 minutes while maintaining the temperature below about15° C. Cool to 0° C. After stirring for 20 minutes at 0° C., slowly add37% aqueous formaldehyde (289 mL, 1.3 eq.) over about 15 minutes. Add6-fluoroindole (400 g, 2.96 mol, 1 eq.) in four portions over about 15minutes. After 30 minutes, divide the reaction mixture into twoportions. To one portion, slowly 1149 g (75% of total mass) over 30minutes to 3 L of 10% NaOH and stir at room temperature. After 18 hours,collect the solid that forms, wash three times with 200 mL of water, dryby suction to give wet 3-(N,N-dimethylaminomethyl)-6-fluoroindole.

Dilute another portion of the reaction mixture (383 g, 25% of totalmass) with aqueous NaOH till pH 12-13 to give a solid. After 30 minutes,collect the solid by filtration, wash with water, dry at 50° C.overnight to give 3-(N,N-dimethylaminomethyl)-6-fluoroindole.

Combine KCN (50.8 g, 0.78 mol),3-(N,N-dimethylaminomethyl)-6-fluoroindole (100 g, 0.52 mol), DMF (400mL) and water (200 mL). Heat to reflux. Evolution of gas begins at about70° C. Maintain the reflux for 4 hours. Cool the reaction mixture toroom temperature, dilute with water and toluene and stir for 10 minutes.Decant the organic layer and wash successively with of saturated aqueoussodium bicarbonate and of 2M aqueous hydrochloric acid. Concentrate todryness the organic layer to give2-(6-fluoro-1H-indol-3-yl)acetonitrile.

Combine 2-(6-fluoro-1H-indol-3-yl)acetonitrile (165 g, 0.925 mol) andTHF (1.32 L). Slowly add 1M solution of BH₃ (2.042 L, 1,832 Kg, 0.131mol) in THF over about 40 minutes. When the addition is complete, heatto reflux within 1 hour. After 1 hour at reflux, cool to roomtemperature and the reaction mixture, over about 25 minutes, to awell-stirred 15% aqueous solution of NaOH (1.9 L, 9.5 mol). Afteraddition, slowly and gradually heat to 50° C. After 1 hour, heat 60° C.After 30 minutes, heat to reflux for 1 hour. Cool to room temperatureand stir overnight, decant the alkaline aqueous layer and replace bywater. Heat to 30° C. under a pressure of 200 mbars in order to distillthe THF until about 2.5 kg of distilate is removed. Extract the mixturewith dichloromethane. Slowly add to the combined organic layers over a25 minutes a mixture of 37% aqueous HCl (143 g) and water (220 g) andstir to give a solid. After 1 hour, collect the solid by filtration,wash with of dichloromethane, and dry overnight to afford of thehydrochloride salt of the title compound.

Combine 6-fluorotryptamine hydrochloride (100 g, 0.437 mol), 2% w/w NaOH(2.5 kg), and dichloromethane (1.5 L) and stir. After 15 minutes, decantthe organic layer, extract the aqueous layer with dichloromethane,combine organic layers, and concentrate to give a residue. Combine theresidue and isopropanol and evaporate in vacuo to give the titlecompound.

EXAMPLE 782N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylamine

Combine isopropanol (500 g), 2,2,3,3-tetrafluoropropylbenzaldehyde(116.8 g), and 6-fluorotryptamine (1.15 equiv.). Heat to reflux overabout 1.5 hour. After 30 minutes at the reflux, distill and over 30minutes collect about 380 g of distillate. Cool the reaction mixture to50° C. and add NaBH₄ (19.71 g) in one portion. After 1 hour at 50° C.,slowly add water over 15 minutes and allow the resulting solution tocool to room temperature overnight. Distill the isopropanol underreduced pressure to give a residue and extract with dichloromethane,combine organic layers, and treat with 1N aqueous HCl (650 mL) to give asolid. Stir the heavy suspension for 2 hours at 20-25° C. Collect thesolid by filtration, wash with dichloromethane and dry at 50° C. undervacuum overnight to afford title compound.

EXAMPLE 783A 3-(2,2,2-Trifluoroethoxy)benzaldehyde

Combine 3-hydroxybenzaldehyde (134.3 g), potassium carbonate (304.0 g),2,2,2-trifluoroethyl p-toluenesulfonate (293.6 g) and dimethylformamide(2 L). Heat the mixture at 90° C. After 15 hours, cool to roomtemperature, pour on ice-water, and extract with dichloromethane.Combine the organic layers, wash with 1N sodium hydroxide, and then withwater. Dry the organic phase over magnesium sulfate, filter, andconcentrate to a residue. Dissolve residue in toluene (200 ml),Chromatograph on silica gel eluting sequentially with toluene and thenethyl acetate to give a residue. Distill the reside under reducedpressure using a Claisen flask equipped with a Vigreux column givestitle compound: bp 0.8 mm Hg, 84-85° C. Redistilling some fractionsusing a Claisen flask equipped with a Vigreux column and subsequently anadiabatic column filled with Rasching rings gives title compound: bp0.9-1.0 mm Hg, 74-76° C.

EXAMPLE 783B 3-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde

Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (200 g, 0.664 mol),3-hydroxybenzaldehyde (101.7 g, 0.833 mol), dimethylformamide (1.5 L)and powdered potassium carbonate (192 g). Heat under stirring at 92° C.for about 22 h. Cool the reaction mixture to 40° C., pour over ice-waterand extract with ethyl acetate. Combine organic phases, wash with 1 Nsodium hydroxide (1 L and 0.5 L) and then a solution of saturated sodiumhydrogen carbonate, dry over magnesium sulfate, filter, evaporate todryness to provide a oily residue. Distill the oily residue underreduced pressure in a Claisen flask to give a first fraction of thetitle compound: bp 108-110° C. under 0.4-0.5 mmHg and a second fractionat 110-111° C. under 0.4-0.5 mmHg.

EXAMPLE 784 3-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde

Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (5.72 g, 17.2 mmol),3-hydroxybenzaldehyde (2.44 g, 20.0 mmol), dimethylformamide (36 ml) andpowdered potassium carbonate (3.03 g) and heat at 110° C. for 10 h. Coolto 20° C. Pass through a bed of aluminium-oxide-90 (57.2 g, 70-230 mesh,grade II-III, Brockmann: Merck #1.01097) and elute with toluene (120ml). Wash the eluted organic phase with 1N HCl (36 ml) and then water.Evaporate the organic layer under reduced pressure to give the titlecompound.

EXAMPLE 785 2-(5-Chloro-1H-Indol-3-yl)-2-oxo-acetyl chloride

Combine 5-chloroindole (20 g, 0.13 mole) and dibutyl ether (230 mL) andcool to 5° C. and slowly add the oxalyl chloride (20.08 g, 0.16 mole)over 15 min while maintaining the temperature between 5° C. and 10° C.Warm to room temperature and stir for 1 hour to give a solid. Cool to 5°C. and stir for 15 minutes, collect the solid by filtration, wash withdibutyl ether, and dry under vacuum to give the title compound.

EXAMPLE 786 (2-(5-Chloro-1H-Indol-3-yl)-2-oxoacetamide

Combine 2-(5-chloro-1H-indol-3-yl)-oxo-acetyl chloride (28.9 g, 0.12mole) and NH₄OH 1N solution (720 ml) to give a suspension. After 18hours, filter, wash with water, and dry under vacuum to give the titlecompound.

EXAMPLE 787 5-Chlorotryptamine

Cool to 5° C., a suspension of LiAlH₄ (40.97 g) in THF (700 ml). Add asolution of AlCl₃ (53.9 g, 0.40 mole) to THF (645 ml) over about 30minutes while maintaining the temperature at about 5° C. and 10° C. Add(2-(5-chloro-1H-Indol-3-yl)-2-oxo-acetamide (20 g, 0.09 mole) in THF(900 ml) while maintaining the temperature at between 5° C. and 7.5° C.When the addition is complete warm to room temperature. Stir overnightand then cool to 7° C. and slowly add a solution of NaOH 50% (342 g,4.28 mol). After stirring for about 1 hour, add anhydrous Na₂SO₄ (30 g)and filter the suspension on a celite bed. Evaporate the filtrate todryness to give an oil. Combine the and Et₂O (500 mL) and add a solutionof Et₂O/HCl 4.5N (15 mL) at room temperature to give a solid. Stir thesuspension at room temperature for 1 hour, filter, and wash with 50 mLEt₂O, dry under vacuum at 50° C. to give the hydrochloride of the titlecompound.

Add 5-chlorotryptamine hydrochloride (15 g, 0.06 mole) water (150 ml),NaOH 1N (75 ml), and dichloromethane (350 mL). Stir the mixture at roomtemperature for 30 minutes, and separate the phases. Wash the aqueousphase with dichloromethane, combine the organic phases, dry over MgSO₄,filter, and evaporate to dryness under vacuum to give the titlecompound.

EXAMPLE 789N-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoro-propoxy)benzylamine

Combine 5-chlorotryptamine (12.1 g, 0.0621 mol) and3-(2,2,3,3-tetrafluoropropoxybenzaldehyde (17.6 g, 0.0621 mole) in EtOH(340 mL). Add molecular sieves and heat to reflux and stir for 4 h. Coolthe mixture to room temperature and add NaBH₄ (7 g, 0.1876 mol) in 3portions. Stir the for 1 h at room temperature. Filter the solid andevaporate the filtrate to a weight of about 90 g, add water, and extractwith dichloromethane. Dry the combined organic layers over MgSO₄,filter, and remove the solvent under reduced pressure to afford thetitle compound.

Combine the title compound (27.6 g) and isopropanol (300 mL). Add asolution of oxalic acid (6 g) in isopropanol (60 mL) to give asuspension. Heat the suspension to reflux and stir for 30 min and thencool to room temperature. Stir for 1 hour at room temperature. collectthe solid by filtration, wash with isopropanol, and dry under vacuum toafford the oxalate of the title compound.

EXAMPLE 790N-2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,-tetrafluoro-propoxy)benzylamineL-tartaric salt

CombineN-2-(5-chloro-1H-indol-3-yl)ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzylamineoxalic acid salt and dichloromethane (700 mL) and add NaOH 1N(150 mL),water (450 mL) and MeOH (190 mL). Stir the mixture for 1 h at roomtemperature. Separate the layers. Add water (200 mL) to the aqueousphase and extract with dichloromethane, combine the organic layers, dryover MgSO₄, filter, and evaporate under vacuum to afford 19.4 g ofN-2-(5-chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

CombineN-2-(5-chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine(19.4 g) in isopropanol (125 mL) and warm to dissolve. Add a solution ofL-tartaric acid (7.02 g) in isopropanol (70 HL). Add seeding crystalsand stir to give a solid. After 2.5 hours, collect the solid byfiltration, wash with isopropanol, and dry under vacuum at 45° C. toafford the title compound.

By the method of Example 221 the following compounds were prepared,isolated as the maleate except where noted:

No. Z′ R₄ Data 791 6-bromo 2,2,3,3- mp 162-164° C. Analysis forC₂₄H₂₃BrF₄N₂O₅: tetrafluoro Calcd: C, 50.10; H, 4.03; N, 4.87; found: C,propyl 50.24; H, 4.02; N, 4.87. 792 6-bromo 2,2,2-trifluoro mp 168-171°C. Analysis for C₂₃H₂₂BrF₃N₂O₅: ethyl Calcd: C, 50.84; H, 4.08; N, 5.16;found: C, 51.02; H, 4.13; N, 5.21. 793 6-methane 2,2,3,3- mp 233-235° C.MS (ACPI): m/e 459.1 (M + 1). sulfonyl tetrafluoro Analysis forC₂₁H₂₃ClF₄N₂O₃S: Calcd: C, 50.96; propyl H, 4.68; N, 5.66; found: C,50.87; H, 4.65; N, 5.64. (isolated as the hydrochloride) 794 6-methane2,2,2-trifluoro mp 234-236° C. MS (ACPI): m/e 427.0 (M + 1). sulfonylethyl Analysis for C₂₀H₂₂ClF₃N₂O₃S: Calcd: C, 51.89; H, 4.79; N, 6.05;found: C, 51.84; H, 4.79; N, 6.10. (isolated as the hydrochloride) 7956-benzene 2,2,3,3- mp 213-215° C. MS (ACPI): m/e 521.0 (M + 1). sulfonyltetrafluoro Analysis for C₂₆H₂₅ClF₄N₂O₃S: Calcd: C, 56.07; propyl H,4.52; N, 5.03; found: C, 55.81; H, 4.66; N, 4.96. (isolated as thehydrochloride) 796 6-benzene 2,2,2-trifluoro mp 231-233.5° C. MS (ACPI):m/e 489.0 (M + 1). sulfonyl ethyl Analysis for C₂₅H₂₄ClF₃N₂O₃S: Calcd:C, 57.20; H, 4.61; N, 5.34; found: C, 56.98; H, 4.63; N, 5.21. (isolatedas the hydrochloride)

EXAMPLE 799 6-Methanesulfonyl-1H-indole

Dissolve 6-Methanesulfonyl-indol-1-ol (5.0 g, 23.7 mmol) in triethylphosphite (35 ml) and heat at 1600 for 5 hours. Cool the solution toambient temperature and dilute with diethyl ether. Wash the ethersolution with brine and water followed by drying (sodium sulfate) andreducing to residue. Crystallize the residue from warm ethyl acetate togive the title compound as colorless cubes: mp 149-152° C. MS (ACPI):m/e 196.0 (M+1). Analysis for C₉H₉NO₂S: Calcd: C, 55.37; H, 4.65; N,7.17; found: C, 55.14; H, 4.71; N, 7.20.

EXAMPLE 800 6-Benzenesulfonyl-1H-indole

Dissolve 6-Bromoindole (6.0 g, 30.6 mmol) in T-F (100 ml) and cool themixture to −10°. Slowly add 60% NaH in mineral oil (3.67 g). After 1hour, add triisopropylsilyltrifluoromethane sulfonate (9.9 ml, 36.7mmol) slowly, remove the cooling bath, and stir for 24 hours. Quenchexcess NaH with ice and remove the THF under vacuum. Dilute theremaining residue with water and extract with dichloromethane. Combine,wash (brine), dry (sodium sulfate), and reduce the extracts to residue.Purify the residue on silica gel using 60% hexanes/dichloromethane togive a yellow oil.

Cool a solution of 6-bromo-1-triisopropylsilanyl-1H-indole (5.5 g, 15.7mmol) in 100 mL anhydrous THF to −78° C. under nitrogen and treat with1.7 M t-butyl lithium (20.5 mL, 34.5 mmol) while keeping the temperatureat −78° C. After the addition, slowly add phenylsulfonyl fluoride (2.1ml, 17.3 mmol) and stir for 30 minutes at −78° C. Warm the mixture toambient temperature and stir for 1 hour. Quench excess t-butyl lithiumwith ice and dilute the mixture with water followed by extraction withethyl acetate. Combine, wash (brine), dry (sodium sulfate), and reducethe extracts to residue. Purify the residue on silica gel using 50%hexanes/dichloromethane to give the product as a white solid.

Dissolve the resulting white solid in THF (50 ml) and treat the solutionwith 1 M tetrabutylammonium fluoride (18.1 mL) and 1 M boric acid (18.1ml). After stirring for 1.5 hours at ambient temperature, dilute themixture with water and extract with ethyl acetate. Combine, wash(brine), dry (sodium sulfate), and reduce the extracts to residue.Purify the residue on silica gel using 1% methanol/dichloromethane togive the title compound as a white solid: mp 141-144° C. MS (ACPI): m/e258.0 (M+1). Analysis for C₁₄H₁₁NO₂S: Calcd: C, 65.35; H, 4.31; N, 5.44;found: C, 64.99; H, 4.31; N, 5.39.

By the method of Example 440 the following compounds were prepared andisolated as the hydrochloride except where noted:

No. Z′ R₄ Data 802 7-Chloro 2,2,3,3- ISMS 415 (M + 1); ¹H NMR(DMSO-d6-HCl salt) 11.3 (bs, 1H), tetrafluoro 9.4 (bs, 2H), 7.6-7.5 (m,1H), 7.45-7.3 (m, 3H), 7.25-6.95 (m, propyl 4H), 6.9-6.5 (m, 1H),4.7-4.5 (m, 2H), 4.2 (bs, 2H), 3.25 (bs, 4H) 803 6-Methoxy 2,2,3,3- ¹HNMR (CDCl₃-freebase) 7.99 (bs, 1H), 7.47-7.44 (d, 1H), tetrafluoro7.23-7.19 (m, 1H), 6.94-6.92 (d, 1H), 6.89-6.88 (m, 1H), propyl6.83-6.82 (m, 2H), 6.79-6.75 (m, 2H), 6.19-5.90 (m, 1H), 4.29-4.22 (m,2H), 3.82 (s, 3H), 3.78 (m, 2H), 2.95 (s, 4H), no N—H observed

By the method of Example 270 the following compounds were prepared,isolated as the maleate except where noted:

809 5-(4- phenyl ISMS 437 (M + 1); C₂₉H₂₆FClN₂O•0.2 H2O: fluoro calcd:C, 73.08; H, 5.58; N, 5.88; found: C, phenyl) 72.99; H, 5.38; N, 5.83

EXAMPLE 811N-(2-(5-Methoxy-1H-indol-3-yl)-ethyl)-(3-(3,3,3-trifluoropropoxy)benzyl)amine

Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4A molecular sieves in35 mL EtOH and reflux overnight. Decant the liquid into a separate flaskand treat with 209 mg (5.5 mmol) NaBH₄. Stir the reaction at ambienttemperature for 1 hour. Concentrate under vacuum, and partition between50 mL 1 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with25 ml dichloromethane and combine the organic layers and concentrate todryness. Purify the resulting oil by radial chromatography (SiO₂; 1%MeOH in CHCl₃ mixed with conc. NH₄OH) to afford 705 mg (1.8 mmol; 100%)of the desired compound as an oil. Conversion to it's HCl salt bystirring a solution of the compound in 50 mL 50/50 THF/EtOH with 1 gpolyvinyl pyridine hydrochloride overnight, filtering and concentratingto a solid. Recrystallize the product from EtOAc: Analysis forC₂₁H₂₃F₃N₂O₂.HCl: calcd: C, 58.81; H, 5.64; N, 6.53; found: C, 58.42; H,5.44; N, 6.51; ISMS 393 (M+1).

By the method of Example 811 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 812 5-fluoro 3,3,3-trifluoro Analysis forC₂₀H₂₀F₄N₂O•HCl: propyl calcd: C, 57.63; H, 5.08; N, 6.72; found: C,57.49; H, 5.04; N, 6.76; ISMS 381 (M + 1) 814 5-bromo phenyl Analysisfor calcd: C₂₃H₂₁BrN₂O•HCl•0.5H₂O: found: C, 59.18; H, 4.97; N, 6.00; C,59.18; H, 4.80; N, 5.92 ISMS 422 (M + 1) 815 5-bromo 2,2,3,3- Analysisfor C₂₀H₁₉BrF₄N₂O•HCl: tetrafluoro calcd: C, 48.46; H, 4.07; N, 5.65;propyl found: C, 48.39; H, 3.95; N, 5.55; ISMS 459 (M + 1) 816 5-bromo2,2,3,3,3- Analysis for C₂₀H₁₈BrF₅N₂O•HCl: pentafluoro calcd: C, 46.76;H, 3.73; N, 5.45; propyl found: C, 46.47; H, 3.67; N, 5.46; ISMS 478(M + 1) 817 5-SO₂CH₃ phenyl Analysis for C₂₀H₁₈BrF₅N₂O•HCl•0.5H₂O•0.4C₇H₈: calcd: C, 64.01; H, 5.85; N, 5.57; found: C, 64.09;H, 5.64; N, 5.48 ISMS 421 (M + 1) 818 5-cyano phenyl Analysis forC₂₄H₂₁N₃O•HCl•0.3H₂O: calcd: C, 70.42; H, 5.57; N, 10.27; found: C,70.55; H, 5.41; N, 10.25 ISMS 368 (M + 1) 819 5- phenyl Analysis forcarboxylic C₂₅H₂₄N₂O₃•HCl•0.3H₂O: acid methyl calcd: C, 68.04; H, 5.62;N, 6.35; ester found: C, 68.06; H, 5.64; N, 6.43 ISMS 401 (M + 1) 820 5-2,2,2- Analysis for carboxylic trifluoroethyl C₂₁H₂₁F₃N₂O₃•HCl•0.1H₂O:acid methyl calcd: C, 56.72; H, 5.03; N, 6.30; ester found: C, 56.46; H,4.77; N, 6.04 ISMS 407 (M + 1) 821 5- phenyl ISMS 385 (M + 1);carboxylic Analysis for C₂₄H₂₃N₃O₂• acid amide HCl•0.9H₂O•0.1C₇H₈:calcd: C, 66.32; H, 5.99; N, 9.39; found: C, 66.07; H, 5.68; N, 9.01; ¹HNMR (Free base CDCl₃) δ 8.56 (s, 1H), 8.13 (s, 1H), 7.64-7.62 (m, 1H),7.33-7.22 (m, 4H), 7.10-6.94 (m, 6H), 6.87-6.84 (m, 1H), 6.2 (bs, 1H),5.8 (bs, 1H), 3.77 (s, 2H), 2.99-2.94 (m, 4H), 1.7 (bs, 1H)

EXAMPLE 825 N-2-(5-Nitro-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine

Combine 5-nitrotryptamine (500 mg, 2.4 mmol), 3-phenoxybenzaldehyde (480mg, 2.4 mmol) and 4 g 4A molecular sieves in 30 mL EtOH and refluxovernight. Decant the liquid into a separate flask and treat with NaBH₄(280 mg, 7.2 mmol) at ambient temperature. After 1 hour concentrateunder vacuum and partition the residue between 25 mL 1 N NaOH and 25 mLdichloromethane. Extract the aqueous layer with 25 ml dichloromethaneand dry the combined organic layers over MgSO₄ and concentrate todryness. Purify the resulting oil by radial chromatography (SiO₂; 2%MeOH in CHCl₃) to afford the desired compound as an oil. Convert to theHCl salt by treating a solution of the compound in 10 mL EtOH with 0.25mL 5 N HCl and 40 mL toluene then concentrating to a solid. Analysis forC₂₃H₂₁N₃O₃.HCl.0.2 EtOH: calcd: C, 64.62; H, 5.17; N, 9.75; found: C,64.89; H, 5.40; N, 9.75; ISMS 388 (M+1).

By the method of Example 825 the following compounds were prepared,isolated as the hydrochloride except where noted:

No. Z′ R₄ Data 826 5-butoxy phenyl Analysis for C₂₇H₃₀N₂O₂•HCl•0.4H₂O:calcd: C, 70.77; H, 7.00; N, 6.11; found: C, 70.87; H, 6.84; N, 6.14;ISMS 415 (M + 1) 827 5-benzamide phenyl Analysis forC₃₀H₂₇N₃O₂•HCl•0.2H₂O: calcd: C, 71.83; H, 5.71; N, 8.38; found: C,71.63; H, 5.35; N, 8.09; ISMS 462 (M + 1) 828 5-benzamide 2,2,2-Analysis for C₂₆H₂₄F₃N₃O₂•HCl: trifluoroethyl calcd: C, 61.97; H, 5.00;N, 8.33; found: C, 61.78; H, 5.16; N, 7.97; ISMS 468 (M + 1) 8295-benzamide 2,2,3,3- Analysis for C₂₇H₂₅F₄N₃O₂•HCl: tetrafluoropropylcalcd: C, 60.51; H, 4.89; N, 7.84; found: C, 60.47; H, 4.95; N, 7.49;ISMS 500 (M + 1) 830 5-methane phenyl Analysis forC₂₄H₂₅N₃O₃S•HCl•0.5H₂O•0.5C₇H₈: sulfonamide calcd: C, 63.53; H, 5.86; N,8.08; found: C, 63.57; H, 5.77; N, 7.81; ISMS 436 (M + 1) 831 5-methane2,2,2- Analysis for C₂₀H₂₂F₃N₃O₃S•HCl•0.1H₂O•0.5C₇H₈: sulfonamidetrifluoroethyl calcd: C, 53.68; H, 5.21; N, 7.99; found: C, 53.48; H,5.19; N, 7.72; ISMS 442 (M + 1) 832 5-methane 2,2,3,3- Analysis forC₂₁H₂₃F₄N₃O₃S•HCl•0.1EtOH•0.8C₇H₈: sulfonamide tetrafluoropropyl calcd:C, 54.72; H, 5.31; N, 7.14; found: C, 54.63; H, 5.25; N, 6.99; ISMS 474(M + 1) 833 5-isopropoxy phenyl Analysis for C₂₆H₂₈N₂O₂•1.1HCl•0.1H₂O:calcd: C, 70.58; H, 6.68; N, 6.33; found: C, 70.37; H, 6.31; N, 6.35;ISMS 401 (M + 1) 834 5-isopropoxy 2,2,2- Analysis forC₂₂H₂₅F₃N₂O₂•HCl•0.3H₂O: trifluoroethyl calcd: C, 58.94; H, 5.98; N,6.25; found: C, 59.08; H, 5.78; N, 6.25; ISMS 407 (M + 1) 8355-isopropoxy 2,2,3,3- Analysis for C₂₃H₂₆F₄N₂O₂•HCl•0.3H₂O:tetrafluoropropyl calcd: C, 57.51; H, 5.79; N, 5.83; found: C, 57.66; H,5.55; N, 5.80; ISMS 439 (M + 1) 836 5-ethoxy phenyl Analysis forC₂₅H₂₆N₂O₂•HCl•0.2H₂O: calcd: C, 70.39; H, 6.47; N, 6.57; found: C,70.40; H, 6.32; N, 6.68; ISMS 387 (M + 1) 837 5-ethoxy 2,2,2- Analysisfor C₂₁H₂₃F₃N₂O₂•HCl: trifluoroethyl calcd: C, 58.81; H, 5.64; N, 6.53;found: C, 58.61; H, 5.61; N, 6.52; ISMS 393 (M + 1) 838 5-ethoxy2,2,3,3- Analysis for C₂₂H₂₄F₄N₂O₂•HCl: tetrafluoropropyl calcd: C,57.33; H, 5.47; N, 6.08; found: C, 57.01; H, 5.35; N, 6.03; ISMS 425(M + 1) 839 2,2,2- phenyl Analysis for C₂₅H₂₃F₃N₂O₂•HCl: trifluoro-calcd: C, 62.96; H, 5.07; N, 5.87; ethoxy found: C, 62.76; H, 4.93; N,5.88; ISMS 441 (M + 1) 840 2,2,2- 2,2,2- Analysis for C₂₁H₂₀F₆N₂O₂•HCl:trifluoro- trifluoroethyl calcd: C, 52.24; H, 4.38; N, 5.80; ethoxyfound: C, 52.21; H, 4.28; N, 6.18; ISMS 447 (M + 1) 841 2,2,2- 2,2,3,3-Analysis for C₂₂H₂₁F₇N₂O₂•HCl•0.2H₂O•0.2C₇H₈: trifluoro-tetrafluoropropyl calcd: C, 52.35; H, 4.51; N, 5.22; ethoxy found: C,52.15; H, 4.30; N, 5.58; ISMS 479 (M + 1) 842 5-butyloxy pyridin-2-ylAnalysis for C₂₆H₂₉N₃O₂•2HCl•0.5EtOH•0.3C₇H₈: calcd: C, 64.83; H, 6.81;N, 7.79; found: C, 64.99; H, 6.48; N, 7.47; ISMS 416 (M + 1) 8435-isopropyl 2,2,2- Analysis for C₂₂H₂₅F₃N₂O•HCl: trifluoroethyl calcd:C, 61.90; H, 6.14; N, 6.56; found: C, 61.72; H, 6.14; N, 6.42; ISMS 391(M + 1) 844 5-isopropyl phenyl Analysis for C₂₆H₂₈N₂O•HCl: calcd: C,74.18; H, 6.94; N, 6.65; found: C, 73.82; H, 6.79; N, 6.65; ISMS 385(M + 1) 845 5-benzene phenyl Analysis for C₂₉H₂₆N₂O₃S•2HCl: sulfonylcalcd: C, 67.11; H, 5.24; N, 5.40; found: C, 67.46; H, 5.37; N, 5.09;ISMS 483 (M + 1) 846 5-benzene 2,2,3,3- Analysis forC₂₆H₂₄F₄N₂O₃S•HCl•0.3EtOH•0.2C₇H₈: sulfonyl tetrafluoropropyl calcd: C,57.07; H, 4.86; N, 4.75; found: C, 56.95; H, 4.68; N, 4.77 ISMS 521(M + 1) 847 5-benzene 2,2,2- Analysis for C₂₆H₂₉N₃O₂•HCl•0.6H₂O:sulfonyl trifluoroethyl calcd: C, 56.04; H, 4.74; N, 5.23; found: C,56.05; H, 4.71; N, 5.12; ISMS 489 (M + 1) 848 5-carboxylic 2,2,2-Analysis for C₂₂H₂₃F₃N₂O₃•HCl: acid ethyl trifluoroethyl calcd: C,57.84; H, 5.30; N, 6.13; ester found: C, 57.85; H, 5.17; N, 6.09; ISMS421 (M + 1) 849 5-carboxylic 2,2,3,3- Analysis forC₂₃H₂₆F₃N₃O₂•HCl•0.6H₂O•0.1C₇H₈: acid tetrafluoropropyl calcd: C, 56.84;H, 5.79; N, 8.05; propylamide found: C, 56.65; H, 5.63; N, 7.71; ISMS466 (M + 1) 850 5-carboxylic phenyl Analysis forC₂₇H₂₉N₃O₂•HCl•0.4H₂O•0.2C₇H₈: acid calcd: C, 69.66; H, 6.67; N, 8.58;propylamide found: C, 69.75; H, 6.57; N, 8.38; ISMS 428 (M + 1) 8515-carboxylic 2,2,2- Analysis for C₂₃H₂₆F₃N₃O₂•HCl•0.8H₂O•0.1C₇H₈: acidtrifluoroethyl calcd: C, 57.67; H, 6.00; N, 8.51; propylamide found: C,57.55; H, 5.77; N, 8.43; ISMS 434 (M + 1) 852 5-carboxylic phenylAnalysis for C₂₈H₃₁N₃O₂•HCl•0.7H₂O: acid calcd: C, 68.54; H, 6.86; N,8.56; butylamide found: C, 68.41; H, 6.60; N, 8.37; ISMS 442 (M + 1) 8535-carboxylic 2,2,3,3- Analysis for C₂₅H₂₉F₄N₃O₂•HCl•H₂O: acidtetrafluoropropyl calcd: C, 56.23; H, 6.04; N, 7.87; butylamide found:C, 56.23; H, 5.79; N, 7.84; ISMS 480 (M + 1) 854 H 2,2,3,3- Analysis forC₂₀H₂₀F₄N₂O•HCl•0.5H₂O: tetrafluoropropyl calcd: C, 56.41; H, 5.21; N,6.58; found: C, 56.98; H, 4.93; N, 6.53; ISMS 381 (M + 1) 8555-benzyloxy 2,2,2- Analysis for C₂₆H₂₅F₃N₂O₂•HCl: trifluoroethyl calcd:C, 63.61; H, 5.34; N, 5.71; found: C, 63.46; H, 5.53; N, 5.72; ISMS 455(M + 1) 856 5-benzyloxy 2,2,3,3 Analysis for C₂₇H₂₆F₄N₂O₂•HCl:tetrafluoropropyl calcd: C, 62.01; H, 5.20; N, 5.36; found: C, 62.04; H,5.16; N, 5.36; ISMS 487 (M + 1) 857 6-phenoxy phenoxy ISMS 435 (M + 1);C₂₉H₂₇ClN₂O₂•0.1H₂O: calcd: C, 73.67; H, 5.80; N, 5.93; found: C, 73.49;H, 5.49; N, 5.82 858 6-Phenoxy 2,2,3,3- ISMS 473 (M + 1);tetrafluoropropyl C₂₆H₂₅F₄ClN₂O₂: calcd: C, 61.36; H, 4.95; N, 5.50;found: C, 61.02; H, 4.67; N, 5.42 859 6-Phenoxy 2,2,2- ISMS 441 (M + 1);trifluoroethyl C₂₆H₂₅F₄ClN₂O₂•0.2H₂O: calcd: C, 62.49; H, 5.12; N, 5.83;found: C, 62.27; H, 4.78; N, 5.74 860 5(3- 2,2,3,3- ISMS 474 (M + 1);pyridyloxy) tetrafluoropropyl C₂₅H₂₅F₄Cl₂N₃O₂•0.5 H₂O: calcd: C, 54.06;H, 4.72; N, 7.57; found: C, 53.97; H, 4.76; N, 7.29 861 5-(Pyridinyl-2,2,2- ISMS 442 (M + 1); 3-oxy) trifluoroethyl ¹H NMR (CDCl₃) 8.37-8.36(m, 1H), 8.27-8.26 (m, 1H), 8.01 (bs, 1H), 7.35-7.32 (m, 1H), 7.26-7.24(m, 3H), 7.22-7.18 (m, 2H), 7.08-7.07 (m, 1H), 6.93-6.91 (m, 2H),6.9-6.86 (m, 1H), 6.79-6.76 (m, 1H), 4.31-4.25 (m, 2H), 3.77 (s, 2H),3.77 (s, 4H). Isolated as dihydrochloride salt

EXAMPLE 863 6-Phenoxytryptamine

By using a method similar to Example 422, the title compound wasprepared: ISMS 253 (M+1); ¹H NMR (CDCl₃) 8.1 (bs, 1H), 7.56-7.54 (m,1H), 7.32-7.28 (m, 3H), 7.07-6.98 (m, 4H), 6.89-6.86 (m, 1H), 3.06-3.02(m, 2H), 2.92-2.88 (m, 2H), 1.68 (bs, 2H).

EXAMPLE 864 2-(5-(Pyridin-3-yloxy)-1H-indol-3-yl)-ethylamine

By using a method similar to Example 422, the title compound wasprepared: ISMS 254 (M+1); C₁₅H₁₅N₃O.1.1 C₂H₂O₄.0.2H₂O: calcd: C, 58.04;H, 4.98; N, 11.81; found: C, 58.17; H, 4.62; N, 11.45.

EXAMPLE 865 6-Phenoxy-1H-indole-3-carbaldehyde

By using a method similar to Example 414, the title compound wasprepared: ISMS 238 (M+1); ¹H NMR (CDCl₃) 10.78 (bs, 1H), 9.95 (s, 1H),8.20-8.18 (m, 1H), 7.76-7.75 (m, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m,2H), 7.00-6.95 (m, 3H).

EXAMPLE 866 5-(Pyridin-3-yloxy)-1H-indole-3-carbaldehyde

By using a method similar to Example 414, the title compound wasprepared: ISMS 239 (M+1); C₁₄H₁₀N₂O₂.0.3H₂O: calcd: C, 69.01; H, 4.39;N, 11.50; found: C, 68.91; H, 4.16; N, 11.39.

EXAMPLE 867 3-(3-Methyl-4-nitro henoxy)pyridine

Rinse 35% oil dispersion of KH (12 g, 11 mmol) with 100 mL hexanes twiceand dry under vacuum before cooling in an ice bath. Add 100 mL dry DMFthen a solution of 3-hydroxypyridine (10 g, 105 mmol) in 100 mL DMFdropwise. Treat with a solution of 5-fluoro-2-nitrotoluene (16.3 g, 105mmol) in 50 mL DMF to obtain a dark solution. Stir at ambienttemperature for 1 hour, pour the mixture into 1 liter of brine andextract twice with 200 mL of EtOAc. Combine the extracts and wash twicewith 500 mL brine, dry over MgSO₄ and concentrate to 24 g of a dark oil.Purification by chromatography 20% EtOAc in hexanes give the titlecompound as an oil: ISMS 231 (M+1); C₁₂H₁₀N₂O₃: calcd: C, 62.61; H,4.38; N, 12.17; found: C, 62.63; H, 4.58; N, 12.06.

EXAMPLE 869 3-Ethoxybenzaldehyde

Combine 5.6 g of 3-hydroxybenzaldehyde (46 mmol) and 10.7 g of1-iodoethane (69 mmol) in DMSO (25 mL) and warm to 80° C. and treat with22.4 g of cesium carbonate (69 mmol) portionwise and stir. After 1 hour,pour into 200 mL brine and extract twice with 150 mL diethyl ether.Combine the extracts and wash twice with 200 mL brine, dry over MgSO₄and concentrate under vacuum to give an oil. Purification bychromatography (SiO₂; 2.5% EtOAc in Hexanes) affords 5.73 g (38 mmol;83%) of the desired compound as an oil: ¹H NMR (CDCl₃) 9.94 (s, 1H),7.42-7.41 (m, 2H), 7.36-7.35 (m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q,214), 1.64-1.40 (t, 3H).

EXAMPLE 870 3-Propoxybenzaldehyde

By using a method similar to Example 869, the title compound wasprepared: ¹H NMR (CDCl₃) 9.95 (s, 1H), 7.43-7.41 (m, 2H), 7.37-7.36 (m,1H), 7.17-7.14 (m, 1H), 9.98-3.95 (t, 2H), 1.84-1.79 (m, 2H), 1.05-1.02(t, 3H).

EXAMPLE 872 4-Phenoxy-1-methyl-2-nitrobenzene

Combine phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol(4.5 g, 30 mmol), and Cu(oAC)₂—H₂O (6 g, 30 mmol) in 30 mL CH₂Cl₂ andtreat with 6 g 4A molecular sieves powder. Add Et₃N (15.18 g, 150 mmol)dropwise, and stir the reaction at ambient temperature for 8 days.Dilute with 100 mL CH₂Cl₂ and filter through celite and concentrate todryness. Purification by chromatography using 2% EtOAc in hexanes gavethe desired product as a yellow oil.

EXAMPLE 873 6-Phenoxy-1H-indole

Combine 4-phenoxy-1-methyl-2-nitro-benzene (6 g, 26.2 mmol) and DMFdimethylacetal (15.6 g, 131 mmol) in 60 mL dry DMF and heat at 170° C.for 16 hours. Cool to room temperature and concentrate to dryness.Dissolve residue in 50 mL EtOAc and hydrogenate with 2 g 5% Pd/C andhydrogen for 3 hours at atmospheric pressure. Filter through celite andconcentrate to an oil. Purify by chromatography using Hex/EtoAC toobtain a tan solid: ISMS 210 (M+1)

¹H NMR (CDCl₃) 8.08 (bs, 1H), 7.61-7.59 (m, 1H), 7.34-7.29 (m, 2H),7.18-7.17 (m, 1H), 7.18-7.0 (m, 4H), 6.92-6.89 (m, 1H), 6.56-6.54 (m,1H).

EXAMPLE 874 5-Pyridin-3-yl-1-methyl-2-nitro-benzene

By a method similar to Example 872, the title compound was prepared.

EXAMPLE 875 5-Pyridin-3-yloxy)-1H-indole

By a method similar to Example 873, the title compound was prepared:ISMS 211 (M+1); C₁₃H₁₀N₂O.0.1H₂O: calcd: C, 73.64; H, 4.85; N, 13.21;found: C, 73.76; H, 4.80; N, 13.09.

EXAMPLE 877 N-2-(5-Phenoxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine

Combine 2-(5-phenoxy-1H-indol-3-yl)ethylamine (0.400 g, 1,59 mmol),3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieves 4A (0.40g) and stir in methanol (15 mL) After 4 h, filter the molecular sievesand wash several times with MeOH. To this MeOH solution, add portionwiseNaBH₄ (61.5 mg, 1.59 mmol), stir the resulting mixture at roomtemperature for 1 h. Remove MeOH under vacuum, dilute the residue withCH₂Cl₂/water, extract with CH₂Cl₂, the combine the organic layers anddry over Na₂SO₄. Concentrate in vacuo the solvent, purification onsilica gel (CH₂Cl₂/MeOH) to give the free base of the title compound.React free base with oxalic acid to form the salt: m.p. 196-198° C.; ¹HNMR (300 MHz, DMSO-d6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m,18H), 11.06 (br, 1H); MS (ELECTROSPRAY) Mn/e: 435.3 (M+1); HRMS (ES+)calcd for C₂₉H₂₇N₂O₂ (M+H) 435.2084 found 435.2073.

EXAMPLE 878(3-Phenoxybenzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-carbamic acid tertbutyl ester

Combine (3-phenoxy-benzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-amine(0.96 g, 2.2 mmol) and NaOH (87.7 mg, 2.2 mmol) and dissolve in THF (10mL), stir at room temperature for 15 min. Add di-tert-butyl dicarbonate(0.58 g, 2.64 mmol) in THF (10 mL) and stir. After 2 h, dilute thereaction with water, extract with EtOAc (3×15 mL), dry over Na₂SO₄.Concentrate the organic solvent on vacuum to give the title compound asan oil: ¹H NMR (300 MHz, CDCl₃) 1.36 (s, 9H), 2.85-2.91 (m, 2H),3.89-3.65 (m, 2H), 4.26 (s, 1H), 4.39 (s, 1H) 6.83-7.13 (m, 10H),7.21-7.33 (m, 7H), 8.00 (s, 1H); MS (ELECTROSPRAY) m/e 534.9 (M+1).

EXAMPLE 879N-Methyl-N-2-(5-Phenoxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine

Add slowly 1.0 M solution of LiAlH₄-THF (5.5 mL, 5.5 mmol) to a solutionof (3-phenoxy-benzyl)-(2-(5-phenoxy-1H-indol-3-yl)-ethyl)-carbamic acidtert butyl ester (0.60 g, 1.12 mmol) in 10 mL dry THF. After addition,heat to reflux the reaction mixture. After 2 h, cool to roomtemperature, quench the reaction by adding water 1.5 mL cautiously,followed by 2N NaOH (1.0 mL). Filter the suspension and wash repeatedlywith ether, dry the organic solution over Na₂SO₄ and concentrate invacuo. Purification on silica gel using CH₂Cl₂/MeOH as eluent gives thefree base of the title compound and further reaction with oxalic acid toform the salt: m.p. 174-175° C.; ¹H NMR (250 MHz, DMSO-d6) 2.51(s, 3H),3.00-3.13 (m, 4H), 4.15 (s, 2H), 6.81-7.03 (m, 7H), 7.11-7.42 (m, 11H),11.05 (br, 1H); MS (ELECTROSPRAY) m/e: 449.1 (M+1−C₂H₂O₄).

EXAMPLE 880 N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoroethoxy)benzyl)amine

Combine 2-(6-chloro-1H-indol-3-yl)ethylamine hydrochloride (1.0 g, 4.3mmol) and ethyldiisopropylamine (900 μL, 5.2 mmol) in ethanol (150 mL)and stir at room temperature and treat with3-(2,2-difluoroethoxy)benzaldehyde (856 mg, 4.6 mmol) and anhydroussodium sulfate (12 g) and heat at 78° C. overnight. Cool to roomtemperature and filter. Treat the resulting filtrate with sodiumborohydride (488 mg, 12.9 mmol) and stir the milky-white mixture at roomtemperature overnight. Remove in vacuo the solvent, and purification ofthe crude on silica gel eluting with 10% methanol in dichloromethanegives the free base of the title compound as a light yellow oil.Dissolve a portion of the oil (651 mg, 1.78 mmol) in methanol (15 mL)and treat with a homogenous solution of ammonium chloride (95 mg, 1.78mmol) in methanol (3 mL). Sonicate the resulting solution for 10 minutesbefore removal of the solvent in vacuo to provide an off-white solid.Triturate with diethyl ether containing a few drops of acetonitrile.Filtration and drying of the precipitate afforded the titlehydrochloride as a white solid: mp 131.6-133° C.; ¹H NMR (400 MHz,dmso-d₆): 11.15 (br s, 1H), 9.50 (br s, 2H), 7.57 (d, 1H, J=8.8 Hz),7.39 (d, 1H, J=2.0 Hz), 7.36 (t, 1H, J=8.2 Hz), 7.32 (br s, 1H), 7.26(d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=7.6 Hz), 7.04 (dd, 1H, J=7.8, 2.2 Hz),7.01 (dd, 1H, J=8.4, 2.0 Hz), 6.41 (tt, 1H, J=54.4, 3.4 Hz), 4.32 (td,2H, J=14.8, 3.6 Hz), 4.14 (br s, 2H), 3.11 (br s, 4H); MS (ES+): m/e365.3 (M+1); CHN (for C₁₉H₁₉F₂ClN₂O.HCl.0.3H₂O) calcd: C, 56.11; H,5.11; N, 6.89; found: C, 56.03; H, 4.95; N, 7.18.

EXAMPLE 881N-Methyl-N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2-difluoroethoxy)benzylamine

Combine(2-(6-chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoroethoxy)benzyl)amine(276 mg, 0.76 mmol) and formaldehyde (55.5 μL of a 38% aqueous solution,0.76 mmol) in dichloroethane (15 mL) and stir at room temperature for 10minutes; add in two portions sodium triacetoxyborohydride (321 mg, 1.51mmol) over 10 minutes and stir at room temperature overnight beforediluting with methanol (10 mL) and quenching with one drop of glacialacetic acid. Remove in vacuo the solvent, and redissolve the cruderesidue in methanol and directly load onto a 10 g SCX column. Afterwashing thoroughly with methanol, elute the column with 2 N ammonia inmethanol. Concentrate in vacuo the eluant to give the free base of thetitle compound as a straw-colored oil. Dissolve the free base (239 mg,0.64 mmol) in methanol (20 mL) and treat with a solution of ammoniumchloride (36 mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for10 minutes before removal of the solvent in vacuo to give thehydrochloride salt as a tacky yellow oil. Dissolve the oil in 10 mL of1:1 acetonitrile-water and lyophilize overnight, providing a fluffywhite solid and triturate with diethyl ether (10 mL) and acetonitrile (2drops). Filtration and drying of the resulting precipitate afforded thedesired hydrochloride as a white amorphous solid: mp: 63.8-65.8° C.; ¹HNMR (400 MHz, dmso-d₆): 11.10 (br s, 1H), 7.52 (d, 1H, J=8.4 Hz) 7.36(d, 1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz), 7.20-7.11(m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4 Hz), 6.38(tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H, J=14.4,3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): m/e 378.9 (M+1);CHN (for C₂₀H₂₁ClF₂N₂O.HCl.0.7H₂O) calcd: C, 56.14; H, 5.51; N, 6.55;found: C, 55.72; H, 5.32; N, 7.07.

By the method of Example 319 the following compounds were prepared,isolated as the oxalate except where noted:

No. Z′ R₄ Data 883 4,7-difluoro 2,2,2-trifluoro mp 208.5-210.0° C.; ¹HNMR (400 MHz, dmso-d₆): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H,J=7.8 Hz), ethyl 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H, J=8.0Hz), 7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85-6.91 (m, 1H), 6.67-6.73 (m, 1H),4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12-3.16 (m, 4H). MS (APCI): m/e385.1 (M + 1). CHN (for C₁₉H₁₇F₅N₂O•1HCl) calcd: C 54.23, H 4.31, N6.66; found: C 54.20, H 4.30, N 6.66. 884 4,5,6,7- 2,2,2-trifluoro mp107.2-108.20° C.; ¹H NMR (400 MHz, dmso-d₆): 11.92 (br s, 1H), 7.32 (s,2H), 6.95-6.99 (m, 2H), 6.87 tetrafluoro ethyl (dd, 1H, J=2.4, 8.0 Hz)4.68 (q, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.88 (t, 2H, J=7.2 Hz) 2.75 (t,2H, J=7.2 Hz). MS (ES+): m/e 421.1 (M + 1). CHN (forC₁₉H₁₅F₇N₂O•1HCl•0.20H₂O) calcd: C 53.83, H 3.66, N 6.61; found: C53.75, H 3.33, N 6.54. 885 4,7-difluoro 2,2,3,3 mp 171.8-173.0° C.; ¹HNMR (400 MHz, dmso-d₆): 11.80 (br s, 1H), 9.21 (s, 2H), 7.39 (t, 1H,J=8.0 Hz), tetrafluoro 7.30-7.33 (m, 2H), 7.18 (d, 1H, J=7.6 Hz), 7.10(dd, 1H, J=2.4, 8.0 Hz), 6.85-6.91 (m, 1H), 6.54-6.83 (m, 2H), propyl4.60 (t, 2H, J=13.6 Hz), 4.16 (s, 2H), 3.16 (s, 4H). MS (APCI): m/e417.1 (M + 1). CHN (for C₂₀H₁₈F₆N₂O•1HCl•0.25H₂O) calcd: C 52.53, H4.30, N 6.13; found: C 52.75, H 4.24, N 5.76. 886 4,5,6,7- 2,2,3,3-tetramp 262.5-263.8° C.; ¹H NMR (400 MHz, dmso-d₆): 12.16 (br s, 1H), 9.43(s, 2H), 7.44 (d, 1H, J=2.0 Hz), tetrafluoro fluoropropyl 7.34-7.40 (m,2H) 7.19-7.21 (d, 1H, J=3.6 Hz), 7.08-7.10 (dd, 1H, J=2.0, 8.0 Hz), 6.69(tt, 1H, J=5.2, 52.0 Hz) 4.59 (t, 2H, J=13.4 Hz), 4.15 (s, 2H), 3.16 (s,4H). MS (APCI): m/e 453.1 (M + 1). CHN (for C₂₀H₁₆F₈N₂O•1HCl•0.10H₂O)calcd: C 48.96, H 3.53, N 5.71; found: C 48.74, H 3.33, N 5.61. 8877-trifluoro 2,2,2- mp 173.8-175.6° C. ¹H NMR (400 MHz, dmso-d₆): 11.36(br s, 1H), 9.07 (br s, 1H), 7.87 (d, 1H, J=7.6 Hz), methyltrifluoroethyl 7.45 (d, 1H, J=7.6 Hz) 7.38-7.42 (m, 1H), 7.36 (d, 1H,J=2.4 Hz), 7.28-7.29 (m, 2H), 7.16-7.29 (m, 2H) 7.11 (dd, 1H, J=2.0, 8.0Hz), 4.77 (q, 2H, J=8.8 Hz), 4.15 (s, 2H), 3.12-3.16 (m, 4H). MS (APCI):m/e 417.1 (M + 1). CHN (for C₂₀H₁₈F₆N₂O•1HCl•0.20H₂O) calcd: C 52.63, H4.28, N 6.14; found: C 52.56, H 4.05, N 5.79. 888 7-trifluoro2,2,3,3-tetra mp 154.0-155.8° C.; ¹H NMR (400 MHz, dmso-d₆): 11.35 (brs, 1H), 9.51 (br s, 2H), 7.91 (d, 1H, J=8.0 Hz), methyl fluoropropyl7.36-7.45 (m, 4H) 7.22 (d, 1H, J=8.0 Hz) 7.17 (t, 1H, J=7.6 Hz), 7.09(dd, 1H, J=2.2, 8.0 Hz), 6.69 (tt, 1H, J=5.2, 52.0 Hz), 4.60 (t, 2H,J=13.6 Hz), 4.15 (s, 2H), 3.13-3.20 (m, 4H). MS (ES+): m/e 449.0 (M +1). CHN (for C₂₁H₁₉F₇N₂O•1HCl•0.10H₂O) calcd: C 51.83, H 4.18, N 5.76;found: C 51.54, H 3.97, N 5.68. 889 7-nitro 2,2,2- mp 133.0-134.8° C.;¹H NMR (400 MHz, dmso-d₆): 11.81 (s, 1H), 9.46 (br s, 2H) 8.14 (d, 1H,J=8.0 Hz), 8.11 trifluoroethyl (d, 1H, J=8.0 Hz) 7.45 (d, 1H, J=2.0 Hz)7.39 (t, 1H, J=8.0 Hz), 7.36-7.37 (m, 1H), 7.25 (t, 1H, J=8.0 Hz), 7.21(d, 1H, J=8.0 Hz), ) 7.10 (dd, 1H, J=2.0, 8.0 Hz), 4.78 (q, 2H, J=8.8Hz), 4.15 (s, 2H), 3.12-3.24 (m, 4H). MS (APCI): m/e 394.1 (M + 1). CHN(for C₁₉H₁₈F₃N₃O₃•1HCl•0.80H₂O) calcd: C 51.37, H 4.67, N 9.46; found: C51.02, H 4.43, N 10.19. 890 7-nitro 2,2,3,3-tetra mp 175.0-176.8° C.; ¹HNMR (400 MHz, dmso-d₆): 11.81 (br s, 1H), 9.32 (br s, 2H), 8.13 (d, 1H,J=8.0 Hz), fluoropropyl 8.11 (d, 1H, J=8.0 Hz) 7.45 (d, 1H, J=2.0 Hz)7.39 (t, 1H, J=8.0 Hz), 7.31-7.32 (m, 1H), 7.25 (t, 1H, J=8.0 Hz), 7.20(d, 1H, J=7.6 Hz), ) 7.10 (dd, 1H, J=2.4, 8.4 Hz), 6.69 (tt, 1H, J=5.2,52.0 Hz), 4.60 (t, 2H, J=13.2 Hz), 4.16 (s, 2H), 3.18 (s, 4H). MS(APCI): m/e 426.1 (M + 1). CHN (for C₂₀H₁₉F₄N₃O₃•1HCl•0.90H₂O) calcd: C50.25, H 4.60, N 8.79; found: C 49.98, H 4.38, N 9.47.

EXAMPLE 892 2-(7-Trifluoromethyl-1H-indol-3-yl)-ethylamine

Combine in a 500 mL round bottom flask equipped with magnetic stirring,(2-trifluoromethyl-phenyl)-hydrazine (5.0 g, 28.4 mmol) and4-aminobutyraldehyde dimethyl acetal (4.54 g, 34.1 mmol) and stir. After5 minutes, slowly add 1N HCl (200 mL) and heat the reaction to 85° C.for 2 hours forming an orange-red colored solution. Increase thetemperature to 100° C. for 10 minutes and cool to room temperature. Pourthe reaction mixture over ice and stir for 10 minutes followed byadjustment to pH ˜10 with ammonium hydroxide. Extract the mixture withmethylene chloride, pool the organic phases, dry over sodium sulfate,and concentrate in vacuo to give a dark orange-brown oil. Purificationon a pre-packed, HMDS treated silica column using a step gradient of 9%to 17% methanol in methylene chloride gives the pure title compound asan orange oil: ¹H NMR (400 MHz, dmso-d₆): 11.18 (br s, 1H), 7.82 (d, 1H,J=7.6 Hz), 7.40 (d, 1H, J=7.2 Hz), 7.24 (d, 1H, J=2.0 Hz), 7.13 (t, 1H,J=7.6 Hz) 2.76-2.83 (m, 4H). MS (APCI): m/e 229.0 (M+1), 212.0 (M−NH₂).

EXAMPLE 893 (7-Nitro-1H-indol-3-yl)-acetonitrile

Dissolve in a 500 mL round bottom flask equipped with magnetic stirring,7-nitro indole (4.55 g, 28.1 mmol) in 130 mL of glacial acetic acid andheat to 70° C. Add di-methyl-methylene ammonium iodide (Eschenmoser'ssalt) and stir the mixture at 70° C. After 45 minutes, cool the reactionmixture and remove the solvent in vacuo to give a crude yellow solid.Treat the crude material with 200 mL ammonium hydroxide and extract withethyl acetate. Pool the organic phases and dry over magnesium sulphateand concentrate in vacuo to give the amine intermediate as a yellowcrystalline solid. Immediately dissolve the intermediate in 200 mL ofdimethyl sulphoxide, treat with methyl iodide (4.55 mL, 56.2 mmole), andstir overnight at room temperature. Add potassium cyanide (18.30 g, 281mmol), and 18-crown-6 (226 mg) and stir the mixture at 50° C. for 25minutes. Pour the resulting brown-yellow suspension over ice, stir for10 minutes, saturate with sodium chloride, and extract with ethylacetate. Wash the pooled extracts once with water, twice with brine, dryover sodium sulfate, and concentrate in vacuo to give the title compoundas a yellow-brown solid. No further purification was necessary. ¹H NMR(400 MHz, dmso-d₆): 11.92 (br s, 1H) 8.14 (d, 1H, J=8.0 Hz), 8.12 (d,1H, J=8.0 Hz) 7.53 (d, 1H, J=2.0 Hz) 7.31 (t, 1H, J=8.0 Hz), 4.16 (s,2H), MS (ES−):m/e 200.0 (M−1).

EXAMPLE 894 2-(7-Nitro-1H-indol-3-yl)ethylamine

Dissolve in a 500 mL round bottom flask equipped with magnetic stirring,and a nitrogen inlet, (7-nitro-1H-indol-3-yl)-acetonitrile (5.27 g, 26mmol) in dry tetrahydrofuran (150 mL). Treat the solution with 1M B₃:THF(55 mL, 55 mmol) and stir at room temperature. After 20 hours, quenchthe reaction by the cautious dropwise addition of water (9 mL) and stiruntil foaming and gas evolution has stopped. Concentrate the mixture todryness in vacuo, redissolve in 1 N HCl (300 ml) and extracte with ethylacetate. Basify the aqueous phase 5 N NaOH and extract with ethylacetate. Pool the ethyl acetate extracts and dry over sodium sulfate andconcentrate in vacuo to give the title compound as an orange-brownsolid: ¹H NMR (400 MHz, dmso-d₆): 11.66 (br s, 1H) 8.07 (t, 2H, J=7.6Hz), 7.32 (s, 1H), 7.20 (t, 1H, J=8.0 Hz) 2.79-2.83 (m, 4H), MS(APCI):m/e 189.0 (M−NH₂).

EXAMPLE 895N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-4-fluoro-3-phenoxy-benzylamine

The method of Example 340 gives the hydrochloride of the title compound:mp 173-175° C.; MS(n/e): 379 (M+1), 377 (M−1); Calculated forC₂₃H₂₀F₂N₂O.HCl: Calcd: C, 66.59; H, 5.10; N, 6.75. Found: C, 66.39; H,5.05; N, 6.57.

EXAMPLE 896 N-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-phenoxybenzylamine

The method of Example 340 gives the hydrochloride of the title compound:mp 196-199° C.; MS(m/e): 361 (M+1), 359 (M−1); Calculated forC₂₃H₂₁FN₂O.HCl: Calcd: C, 69.60; H, 5.59; N, 7.06. Found: C, 69.23; H,5.58; N, 7.00.

EXAMPLE 897 4-Fluoro-1-methyl-3-phenoxybenzene

Add triethylamine (28.6 mL, 205 mmol) dropwise to a mixture of2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper(II) acetate (7.46 g,41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol), powdered 4 Å sieves(7 g), and methylene chloride (400 mL). Stir at ambient temperature.After 22 h, filter and concentrate the filtrate. Purify the residue bysilica gel chromatography (50% methylene chloride/hexanes), concentrateand purify again by silica gel chromatography (100% hexanes) to give 2.4g (29%) of the title compound: MS(m/e): 202 (M⁺).

EXAMPLE 898 4-Fluoro-3-phenoxybenzaldehyde

Combine 4-fluoro-1-methyl-3-phenoxybenzenze (2.43 g, 12.0 mmol),N-bromosuccinimide (4.92 g, 27.6 mmol), benzoyl peroxide (408 mg, 1.68mmol), and carbon tetrachloride (55 mL). Heat the mixture at refluxtemperature for 6.5 h and cool to 0° C. for 64 h. Filter the solids andconcentrate the filtrate. Dissolve the residue in chloroform and washwith ice cold sodium carbonate solution. Dry the chloroform solutionover sodium sulfate, filter and concentrate under reduced pressure.Dissolve the residue in acetonitrile (50 mL) and add4-methylmorpholine-4-oxide (4.6 g, 39.1 mmol) and powdered 4 Å sieves(200 mg). Stir at ambient temperature for 20 h, filter and concentrate.Purify by silica gel chromatography (5%, 30% ethyl acetate/hexanes) togive 220 mg (8%) of the title compound: MS(m/e): 216 (M⁺).

EXAMPLE 899 7-Fluorotryptamine

Combine lithium aluminum hydride (12.8 g; 336.1 mmol) and 0° C.anhydrous tetrahydrofuran (160 mL). Cool resulting exotherm to 0° C. Add7-fluoro-3-(2-nitrovinyl)-1H-indole (11.55 g, 56.0 mmol) in anhydrousTHF (200 mL) dropwise. After 30 min, warm to ambient temperature. After4 hours, cool to 0° C. and add saturated sodium sulfate solution (35 mL)dropwise. Filter the solids and wash with THF and ethyl acetate.Concentrate the filtrate and dissolve the residue in methylene chloride.Filter the precipitate to give 1.26 g of product as brown crystals.Concentrate the filtrate and chromatograph on silica gel eluting with5%, 7%, 10% 2N ammonia in methanol/methylene chloride to give product:MS(m/e): 179 (M+1), 177 (M−1); Calculated for C₁₀H₁₁FN₂: Calcd: C,67.40; H, 6.22; N, 15.72. Found: C, 67.06; H, 6.11; N, 15.48.

EXAMPLE 900 3-(2-Nitrovinyl)-6-methanesulfonyl-1H-indole

Combine 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68 mmol) and TFA(9.0 ml) and stir until dissolved. Add 6-methanesulfonyl-1H-indole (1.5g, 7.68 mmol) and stir at ambient temperature. After 24 hours, pour thereaction mixture into ice/water, extract with ethyl acetate, then washethyl acetate with brine and saturated sodium bicarbonate. Filter, wash,and dry the precipitate to give the title compound as a yellow powder:mp>250° C. MS (ACPI): m/e 267.0 (M+1). Analysis for C₁₁H₁₀N₂O₄S: Calcd:C, 49.62; H, 3.79; N, 10.52; found: C, 49.86; H, 3.97; N, 10.25.

EXAMPLE 901 3-(2-Nitrovinyl)-6-benzenesulfonyl-1H-indole

Combine 1-dimethylamino-2-nitroethylene (676.9 mg, 5.83 mmol) and TFA(9.0 ml) and stir until dissolved. Add 6-benzenesulfonyl-1H-indole (1.5g, 5.83 mmol) and stir at ambient temperature. After 24 hours, pour thereaction mixture into ice/water and adjust to pH 8. After stirring,filter the precipitate, wash with water, and dry to give the titlecompound as a yellow powder: mp 110° C., dec. MS (ACPI): m/e 329.0(M+1). Analysis for C₁₆H₁₂N₂O₄S: Calcd: C, 58.53; H, 3.68; N, 8.53;found: C, 58.54; H, 3.83; N, 7.85.

EXAMPLE 902 (3-Phenoxybenzyl)-(2-pyridin-2-yl-ethyl)amine oxalic acidsalt

Combine 2-pyridin-2-yl-ethylamine (Aldrich, 0.36 mL, 3.0 mmol),3-phenoxybenzaldehyde (Aldrich, 0.58 mL, 3.66 mmol), 3A molecular sieves(0.5 g), and methanol (30 mL) and heat to reflux for 4 hours. Remove themolecular sieves by filtration. Add sodium borohydride (0.35 g, 9.0mmol) slowly and stir the reaction at room temperature. After 1 hour,concentrate the reaction and dissolve the residue in a mixture of 1 NNaOH solution and methylene chloride and extract the mixture withmethylene chloride. Wash the organic extract with water, dry (Na₂SO₄)and concentrated to give a pale yellow oil. Form the salt with oxalicacid and crystallize from ethyl acetate to give a white solid:mp=183-185° C.; ms: ion at 305.2.

EXAMPLE 903 (3-[1,3]Dioxolan-2-yl-phenyl)-pyridin-2-ylamine

Combine 2-aminopyridine (8.25 g, 95 mmol),2-(3-bromo-phenyl)-[1,3]dioxolane (13.8 mL, 90 mmol), sodium t-butoxide(12.2 g, 126 mmol), BINAP (210 mg, 0.62 mmol), Pd2(dbu)₃ (630 mg, 0.21mmol) and toluene (100 mL) and heat to reflux for 48 hours. Cool thereaction to room temperature, dissolve in ether and filter andconcentrate the resulting solution. Purification by flash chromatography(hexanes/EtOAc (8.5:1.5) and then hexanes/EtOAc (7:3)) provides thetitle compound as a yellow oil.

EXAMPLE 904 3-(Pyridin-2-ylamino)-benzaldehyde

Dissolve (3-[1,3]dioxolan-2-yl-phenyl)-pyridin-2-yl-anine (10.32 g, 42.6mmol) in THF (150 mL). Add concentrated HCl solution (37.5 mL) and stirthe solution at room temperature overnight. Concentrate the reaction,treat with water, and extract with CH₂Cl₂. Wash the organic extract withwater, dry (Na₂SO₄) and concentrate to give the crude product.Purification by flash chromatography (hexanes/EtOAc (7:3)) provides thetitle compound as a yellow solid.

EXAMPLE 905N-(3-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(pyrid-2-ylamino)benzylamine

Combine 6-chlorotryptamine (0.22 g, 1.1 mmol),3-(pyridin-2-ylamino)benzaldehyde (0.22 g, 1.1 mmol), 3A molecularsieves (0.5 g), and methanol (25 mL) are and heat to reflux for 4 hours.Remove the molecular sieves by filtration. Add sodium borohydride (0.16g, 3.3 mmol) slowly and stir the reaction at room temperature. After 1hour, concentrate the reaction and dissolve the residue in a mixture of1N NaOH solution and methylene chloride and extract the mixture withmethylene chloride. Wash the organic extract with water, dry (Na₂SO₄)and concentrate to give the crude product. Purification by flashchromatography (EtOAc/MeOH (9:1) with 2% concentrated NH₄OH solution)provides the desired product as a colorless oil. Form thedihydrochloride salt and crystallize from EtOAc to give the desiredproduct: mp=164-166° C.; ms: ion at 377.1.

The following compounds were prepared following a procedure followingExample 673:

No: R₁ R₄ Data 906 pyrid-2-yl phenyl LC Method 3: Rf 2.83 min at 54/220nm; m/e 305.0 (M + 1) 907 thien-2-yl phenyl LC Method 3: Rf 4.00 min at254/220 nm; m/e 3309.9 (M + 1)

The following compounds were prepared following a procedure followingExample 673:

No.: Z′ R₄ Data 908 3-Br propyl LC Method 3: Rf 4.48 min at 254/220 nm;m/e 349.9 (M + 1) 908a 3-COOCH₃ phenyl MS = 362 (m + 1), IR; 1718.51,1584.26, 1489.84, 1445.78, 1285.67, 1253.07, 1199.51 cm⁻¹

The following compounds were prepared following a similar procedure inExample 665:

No.: Z′ R₂ Data 909 H isopropyl LC Method 3: Rf 5.43 min at 254/220 nm;m/e 385.0 (M + 1) 910 methoxy methyl LC Method 2: Rf 4.86 min at 254/220nm; m/e 385.0 (M + 1)

By the method of Example 221 the following compounds were prepared,isolated as the maleate except where noted:

No. Z″ R₄ Data 911 3-chloro 2-fluoro- LC Method 3: Rf 4.61 min at254/220 nm; benzyl m/e 369.9 (M + 1) 912 3-chloro 4-fluoro- LC Method 3:Rf 4.62 min at 254/220 nm; benzyl m/e 369.9 (M + 1) 913 3-chloro2,3-difluoro- LC Method 3: Rf 4.76 min at 254/220 nm; benzyl m/e 387.9(M + 1)

EXAMPLE 914 3-Propoxybenzonitrile

Combine 3-hydroxybenzonitrile (11.052 gm; 92.8 mmol), n-propyl bromide(24.4 gm; 198 mmol), and potassium carbonate (38.65 gm; 280 mmol) in2-butanone (175 mL) and heat and reflux. After 17 h, cool the mixture toroom temperature, and decant the solution and concentrate by rotaryevaporation. Partition the residue between diethyl ether (150 mL) andwater (150 mL), separate the layers and extract the aqueous layer withdiethyl ether (2×100 mL). Combine the organic layers and wash withwater, 1 N NaOH, and water, dry over MgSO₄, and concentrate. Distill theresidue to give the title compound.

EXAMPLE 915 3-Propoxybenzylamine hydrochloride

Combine 100 mL of lithium aluminum hydride (1 M in THF) and 50 mL of THFand add sulfuric acid (100%) dropwise at 10° C. Allow the mixture towarm to room temperature and stir. After a 1 h period, remove the solidsby filtration through diatomaceous earth using nitrogen pressure, and tothe clear solution add dropwise a solution of nitrile in 50 mL of THF at0° C. Allow the reaction to stir. After 1 h at 0° C., allow to warm toambient temperature and stir over a 2.5 h period. Cool the reaction to0° C. and add dropwise 16 mL of a 1:1 solution of water/THF, and adddropwise addition of 2 M NaOH (60 mL). Filter the resulting mixture,wash the solids with THF (2×100 mL), combine the organic layers dry oversodium sulfate and concentrate. Dissolve the residue in dry ether (250mL) and acidify with HCl/dioxane solution (20 mL of 4 M solution). Washthe resulting solid with ether to yield the title compound as a whitesolid.

EXAMPLE 916 2-(3-Bromophenyl)-N-(3-propoxybenzyl)acetamide

Combine 3-propoxy-benzylamine in 50 mL of dichloromethane and adddropwise to a mixture of 3-bromophenylacetyl chloride (4.90 gm; 21.0mmol) and triethylamine (3.60 gm; 35.9 mmol) in 250 mL ofdichloromethane at 0° C. Allow the reaction to warm to room temperatureand stir for 18 h. Pour the reaction into 100 mL of saturated brine,separate the layers and extract the aqueous layer with 100 mL ofdichloromethane. Combine organic layers, wash with brine, dry (MgSO₄),and concentrate. Purification by chromatography on silica gel with 40%EtOAc in hexanes gives the title compound.

EXAMPLE 917 2-(4′-Fluorobiphenyl-3-yl)-N-(3-propoxybenzyl)acetamide

Combine bromoamide (0.365 gm; 1.008 mmol), 4-fluorophenylboronic acid(0.175 gm; 1.25 mmol), cesium fluoride (0.360 gm; 2.37 mmol), anddichloro(bistriphenylphosphine)palladium(II) (0.062 gm; 0.088 mmol) inNMP (3 mL) and heat at 104° C. After 13.3 h. cool to ambient temperatureand dilute with 40 mL each of dichloromethane and water. Separate thelayers and extract the aqueous layer with dichloromethane (2×20 mL).Combine the organic layers, wash four times with 10 mL portions ofsaturated brine, dry (MgSO₄) and concentrate. Purification bychromatography on silica gel with 40% EtOAc in hexanes gives the titlecompound.

EXAMPLE 918 N-(2-(3-(4-Fluorophenyl)phenyl)ethyl)-3-propoxybenzylamine

Combine 2-(4′-fluorobiphenyl-3-yl)-N-(3-propoxybenzylacetamide in 15 mLof THF and add a solution of BH₃—SMe₂ (2 M in THF) dropwise at 0° C.Allow the reaction to warm to ambient temperature and stir. After 5 h.Cautiously add ethanol (1 mL), and concentrate the mixture. Dissolve theresidue in ethanol (2 mL), heat to reflux for 2 h, and concentrate.Purification using gives the title compound as a tan solid. Dissolve theamine in 10 mL of 1:1 dichloromethane/methanol and add 600 mg ofpolyvinylpyridine hydrochloride. Shake the mixture for 4 h, removed byfiltration the polymer and concentrate the residue and wash with etherto give the title compound as the hydrochloride: MS (ES+): m/e 364(M+1).

EXAMPLE 919 N-(2-(5-Benzyloxy-1H-indol-3-yl)-ethyl)-3-phenoxybenzylamine

Combine 5-benzyloxy tryptamine (1.23 g, 4.6 mmol), 3-phenoxybenzaldehyde(97%, 1.09 g, 5.53 mmol) and molecular sieves 4A (1.0 g) and stir inmethanol (15 mL) for 4 h. Filter the molecular sieves and wash severaltimes with MeOH. To this MeOH solution, add portionwise NaBH₄ (174 mg,4.60 mmol), stir the resulting mixture at room temperature for 1 h.Remove MeOH under vacuum, dilute the residue with CH₂CL₂/water, extractwith CH₂Cl₂, combine organic layers, dry over Na₂SO₄ and concentrate thesolvent in vacuo. Purification by silica gel chromatography(CH₂Cl₂/MeOH) to give the free base. Combine the free base with oxalicacid to form the salt: (300 MHz, DMSO-d₆) 2.95-3.15 (m, 4H), 3.93 (s,2H), 4.10 (br, 1H), 5.05 (s, 2H), 6.85-7.46 (m, 18H), 10.67 (br, 1H); ms(ELECTROSPRAY) m/e: 449.2 (M+1).

EXAMPLE 921N-(2-(5-Benzyloxy-1H-indol-3-yl)ethyl)-N-methyl-3-phenoxy-benzylamine

Combine N-(2-(5-benzyloxy-1H-indol-3-yl)ethyl)-3-phenoxy-benzylamine(1.61 g, 3.59 mmol) and NaOH (143.6 mg, 3.59-1.75 mmol) and dissolve inTHF (25 mL) and stir at room temperature. After 15 min., adddi-tert-butyl dicarbonate (1.57 g, 7.18 mmol) in THF (20 mL) and heat toreflux for 4 h. Remove the solvent, dilute with water, extract withCH₂Cl₂, (3×15 mL), dry over Na₂SO₄ and concentrate in vacuo to give abrown oil. The crude product was used directly in the next step withoutpurification.

Combine 1.0 M solution of LiAlH₄-THF (13.4 mL, 13.4 mmol) and(3-phenoxy-benzyl)-(2-(5-benzyloxy-1H-indol-3-yl)-ethyl)-carbamic acidtert-butyl ester (1.83 g, 3.34 mmol) and slowly add 15 mL dry THF. Afteraddition, heat the reaction mixture to reflux. After 4.5 h, cool down toroom temperature. Quench the reaction by adding water (1.5 mL)cautiously, followed by 10% NaOH. Filter off the suspension and washrepeatedly with ether. Dry the organic solution over Na₂SO₄ andconcentrate the solvent in vacuo. Purification by silica gelchromatography using CH₂Cl₂/MeOH as eluent to give the free base: ¹H NMR(300 MHz, CDCl₃) 2.35 (s, 3H), 2.69-2.74 (m, 2H), 2.91-2.96 9m, 2H),3.65 (s, 2H), 5.07 (s, 2H), 6.90-7.53 (m, 18H), 7.80 (s, 1H). Thiscompound reacted further with oxalic acid to form the salt.

EXAMPLE 922N-(2-(6,7-Difluoro-1H-indol-3-yl)-ethyl)-3-(pyridin-4-yloxy)benzylamine

Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol),3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) andmolecular sieves 4A (0.30 g) and stir in methanol (12 mL). After 4 h.filter the molecular sieves and wash several times with MeOH. To thisMeOH solution, add portionwise NaBH₄ (55.0 mg, 1.45 mmol), and stir atroom temperature for 1 h. Remove MeOH in vacuo, dilute the residue withCH₂Cl₂/water, extract with CH₂Cl₂, combine organic layers, dry overNa₂SO₄ and concentrate in vacuo. Purification by flash chromatography onsilica gel (CH₂Cl₂/MeOH) to give the free base which is converted to thehydrochloride salt: ¹H NMR (300 MHz, DMSO-d₆) 3.13 (s, 4H), 4.20 (s,2H), 6.85-7.55 (m, 10H), 8.47-8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br,1H): MS (electrospray) m/e: 380.2 (M+1−HCl), 378.3 (M−1−HCl).

The present invention also provides novel intermediates of the compoundsof formula I. The present invention provides intermediates of formulaIII:

wherein

R₃ is selected from the group consisting of hydrogen, fluoro, andmethyl;

R_(4′) is fluorinated C₂-C₄ alkyl.

The present invention also provides novel crystalline forms of thecompounds of formula I. Thus, for example,N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride may be prepared by crystallization under controlledconditions to give novel crystalline forms. Crystallization from asolution and slurrying techniques are contemplated to be within thescope of the present process. In practice, a number of factors caninfluence the form of(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride obtained, including temperature and solvent composition.While the precise conditions under which crystalline(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride is formed may be empirically determined it is onlypossible to give a number of methods which have been found to besuitable in practice. A preferred polymorphic form ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride can be prepared by crystallization or slurry from diethylether. Another preferred polymorphic form ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminehydrochloride can be prepared by crystallization from aqueousdichloromethane, aqueous acetone, ethyl acetate, ethylacetate/cyclohexane, ethyl acetate/hexane, ethyl acetate/heptane,acetone/cyclohexane, isopropanol/hexanes, acetonitrile,acetonitrile/toluene, n-propanol/isoamylacetate/hexane, isopropylacetate/diethyl ether, methyl t-butyl ether/acetone, water,water/acetone, water/diethyl ether.

Crystalline(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminemay be prepared by direct crystallization under controlled conditions.The novel crystalline forms of the present invention may also beprepared by dissolving(N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylaminein a solvent and then forming the hydrochloride salt by the addition ofa solution containing hydrochloric acid and then allowingcrystallization while controlling the temperature.

A number of methods are available to characterize crystalline forms oforganic compounds. For example methods include differential scanningcalorimetry, solid state NMR spectrometry, infra-red spectroscopy, andX-ray powder diffraction. Among these X-ray powder diffraction and solidstate NMR spectroscopy are very useful for identifying anddistinguishing between crystalline forms.

X-ray powder diffraction analysis are performed by a variety of methodsknown to the skilled person. These methods can be varied to increasesensitivity by sample preparation techniques and by using more intenseradiation, smaller scan steps, and slower scan rates. One method is asfollows. Either with or without lightly grinding the sample with anagate mortar and pestle, the sample is loaded into a sample holder forthe X-ray powder diffraction measurement. The X-ray powder diffractionpatterns are measured using a Siemens D5000 X-ray powder diffractometerequipped with a CuK_(α) source (λ=1.54056 Å) operated at 50 kV and 40 mAusing divergence slit size of 1 mm, receiving slit of 1 mm, and detectorslit of 0.1 mm. Samples can be scanned between 4° and 35° (2θ) with astep size of 0.020 and a maximum scan rate of 3 sec/step. Data iscollected using a Kevex solid-state silicon lithium detector. Optimally,a silicon standard is run routinely to check the instrument alignment.

It is well known in the crystallography art that, for any given crystalform, the relative intensities and peak widths of the diffraction peaksmay vary due to a number of factors, including the effects of preferredorientation and/or particle size. Where the effects of preferredorientation and/or particle size are present, peak intensities may bealtered, but the characteristic peak positions of the polymorph areunchanged. See, e.g., The United States Pharmacopoeia #24, NationalFormulary #19, pages 1843-1844, 2000.

Grinding may be used to minimize peak intensity. However, if grindingsignificantly alters the diffractogram or alters the crystalline stateof the sample, then the diffractogram of the unground sample should beused. Grinding is done in a small agate mortar and pestle. The mortar isheld during the grinding and light pressure was applied to the pestle.

Thus, a properly prepared sample crystalline compound of formula I maybe characterized by one or more 2θ values in an X-ray diffractionpattern obtained as described above.

Crystalline compounds of formula I may also be characterized by solidstate NMR spectroscopy. Solid state ¹³C chemical shifts reflect not onlythe molecular structure of but also the electronic environment of themolecule in the crystal.

Solid state NMR (¹³C) analysis can be carried out using ¹³C Crosspolarization/magic angle spinning (CP/MAS). NMR (solid-state NMR orSSNMR) spectra are obtained using a Varian Unity 400 MHz spectrometeroperating at a carbon frequency of 100.580 MHz, equipped with a completesolids accessory and Varian 7 mm VT CP/MAS probe. Acquisition parametersare readily determined and typically are 90° proton r.f. pulse width 4.0Vs, contact time 1.0 ms, pulse repetition time 5 s, MAS frequency 7.0kHz, spectral width 50 kHz, and acquisition time 50 ms. Chemical shiftsare generally reported by referenced to the methyl group of externalhexamethylbenzene, that is, by sample replacement withhexamethylbenzene.

Thus, crystalline compounds of formula I may be characterized one ormore resonances in the solid state ¹³C nuclear magnetic spectra obtainedas described above.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition, that is, combined withpharmaceutically acceptable carriers or excipients. The compounds of thepresent invention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts, forpurposes of stability, convenience, solubility, and the like. Inpractice, the compounds of formula I and II are usually administered inthe form of pharmaceutical compositions, that is, in admixture withpharmaceutically acceptable carriers or diluents.

Thus, the present invention provides pharmaceutical compositionscomprising a compound of the formula I or II and a pharmaceuticallyacceptable diluent.

The compounds of formula I and II can be administered by a variety ofroutes. In effecting treatment of a patient afflicted with disordersdescribed herein, a compound of formula I and II can be administered inany form or mode which makes the compound bioavailable in an effectiveamount, including oral and parenteral routes. For example, compounds offormula I and II can be administered orally, by inhalation,subcutaneously, intramuscularly, intravenously, transdermally,intranasally, rectally, occularly, topically, sublingually, buccally,and the like. Oral administration is generally preferred for treatmentof the disorders described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, the solubility andchemical properties of the compound selected, the chosen route ofadministration, and other relevant circumstances considered in standardpharmaceutical practice. (Remington's Pharmaceutical Sciences, 18thEdition, Mack Publishing Co. (1990)).

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention may be determined by a person skilled in the art.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other coatingagents. A syrup may contain, in addition to the present compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about90% of the weight thereof. The amount of the compound of formula I andII present in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment, or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations may contain aconcentration of the formula I and II or its pharmaceutical salt fromabout 0.1 to about 10% w/v (weight per unit volume).

The compounds of formula I and II are antagonists of 5-HT₆ receptors.Such antagonism can be identified by the methods below.

EXAMPLE A

Assay for 5HT₆ binding

The assay buffer used is 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl, 5mM MgCl2, 1 mM EDTA. The radioligand used is 3H-LSD from New EnglandNuclear Cat. #NET 638-75.9 Ci/mmol. The membranes used are from ReceptorBiology, Cat. No. RB-HS6. These are membranes from HEK-293 cellsexpressing the Human 5HT₆ receptor.

Test compounds are obtained as 10 mM stocks in 100% DMSO. They arediluted to 1 mM in 100% DMSO by adding 180 μl DMSO to 20 μl of stock in96 well plates using a multidrop. The 1 mM stocks are then diluted tomake an 11 point concentration range from 125 μM down to 1.25 nM in halflog increments using 10% DMSO as diluent. This is done using a TECANrobot. The final DMSO at this stage is 21.25%.

Radioligand is diluted in assay buffer to make a 125 nM solution andeach vial of membranes is diluted up to 92 mL in assay buffer. The finalassay volume is 250 μl consisting of 210 μl of diluted membranes, 20 μlof compound or 21.25% DMSO for total binding, and 20 μl of dilutedradioligand. The compounds are transferred from drug dilution platesinto corning 96 well assay plates using a 96 well Multimek pipettor.Radioligand and membranes are added to assay plates using multidroppipettors. Non-specific binding is determined in wells containing afinal serotonin concentration of 10 μM. In the final assay volume theradioligand is 10 nM and the membrane protein is approximately 25μg/well. The final drug concentration range in half logs is from 10 μMdown to 0.1 nM. The final DMSO in the assay is 1.7%.

After addition of drug, membrane, and ligand, the plates are incubatedfor one hour at room temperature. During this time 96 well Milliporefilter plates (MAFBNOB50) are soaked for a least 30 minutes with 200 μlper well of 0.5% polyethyleneimine.

The 0.5% PEI is removed from filterplate wells using a TiterTek MAPaspirator and 200 μl of the incubation mixture is transferred from theincubation plate to the filterplate after mixing. This transfer is doneusing the 96 tip Mutimek pipettor. After transfer to the filterplatefilterplates are extracted and washed twice with 220 μl per well of coldbuffer on the MAP aspirator. The peel away bottoms are removed from thefilterplates and 100 μl per well of microscint 20 scintillation fluid isadded per well using a multidrop. Plates are placed into suitableholders and are left at room temperature for three hours and are countedfor ³H in either a Wallac Microbeta counter or on a Packard Topcount.

In one embodiment, the present invention provides methods of treatingdisorders associated with the 5-HT₆ receptor, comprising: administeringto a patient in need thereof an effective amount of a compound offormula I. Thus, the present invention contemplates the variousdisorders described to be treated herein and others which can be treatedby such antagonists as are appreciated by those skilled in the art.

In particular, because of their ability to antagonize the 5-HT₆receptor, it is recognized that the compounds of the present inventionare useful for treating cognitive disorders, that is, disordersinvolving cognitive deficits. A number of the disorders which can betreated by 5-HT₆ antagonists are known according to established andaccepted classifications, while others are not.

Some of the disorders to be treated according to the present inventionare not well categorized and classified because cognition is acomplicated and sometimes poorly defined phenomenon. It is, however,widely recognized that cognition includes various “domains.” Thesedomains include short term memory, long term memory, working memory,executive function, and attention.

While many of the disorders which can be treated according to thepresent invention are not uniformly described and classified in the art,it is understood that the compounds of the present invention are usefulfor treatment of disorders characterized by a deficit in any of thecognitive domains listed above or in other aspects of cognition. Thusthe term “cognitive disorders” is meant to encompass any disordercharacterized by a deficit in one or more cognitive domain, includingbut not limited to short term memory, long term memory, working memory,executive function, and attention.

One cognitive disorder to be treated by the present invention isage-related cognitive decline. This disorder is not well defined, butincludes decline in the cognitive domains, particularly the memory andattention domains, which accompany aging. Another is mild cognitiveimpairment. Again, this disorder is not well defined in the art, butinvolves decline in the cognitive domains, and is believed to representa group of patients the majority of which have incipient Alzheimer'sdisease. Also, a wide variety of insults, including stroke, ischemia,hypoxia, inflammation, and infectious processes can result in cognitivedeficits as a sequella which can be treated according to the presentinvention.

Where the disorders which can be treated by 5-HT₆ antagonists are, atpresent, known according to established and accepted classifications,these classifications can be found in various sources. For example, atpresent, the fourth edition of the Diagnostic and Statistical Manual ofMental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool for identifying many ofthe disorders described herein. Also, the International Classificationof Diseases, Tenth Revision, (ICD-10) provides classifications for manyof the disorders described herein. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for disorders described herein, including those not wellcharacterized by the art and those described in the DMS-IV and ICD-10,and that terminology and classification systems evolve with medicalscientific progress.

In one embodiment, the present invention provides methods of treatingdisorders selected from the group consisting of: age-related cognitivedisorder, mild cognitive impairment, mood disorders (includingdepression, mania, bipolar disorders), psychosis (in particularschizophrenia), anxiety (particularly including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), idiopathicand drug-induced Parkinson's disease, epilepsy, convulsions, migraine(including migraine headache), substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders(including narcolepsy), attention deficit/hyperactivity disorder,conduct disorder, learning disorders, dementia (including Alzheimer'sdisease and AIDS-induced dementia), Huntington's Chorea, cognitivedeficits subsequent to cardiac bypass surgery and grafting, stroke,cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia,cardiac arrest, and hypoglycemic neuronal damage, vascular dementia,multi-infarct dementia, amylotrophic lateral sclerosis, and multiplesclerosis, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I or II. That is, the presentinvention provides for the use of a compound of formula I and II orpharmaceutical composition thereof for the treatment disordersassociated with the 5-HT₆ receptor.

It is recognized that the terms “treatment” and “treating” are intendedto include improvement of the cognitive deficit associated with each ofthe disorders associated with the 5-HT₆ receptor described herein. Also,it is also recognized that one skilled in the art may affect thedisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient believed to be susceptible tosuch disorders with an effective amount of the compound of formula I.Thus, the terms “treatment” and “treating” are intended to refer to allprocesses wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the disorders describedherein, but does not necessarily indicate a total elimination of allsymptoms, and is intended to include prophylactic treatment of suchdisorders. For example, the present invention specifically encompassesthe treatment of the cognitive deficits associated with schizophrenia,stroke, Alzheimer's disease, and the other disorders described herein.Thus, it is understood that the present invention includes adjunctivetreatment of the disorders described herein. More specifically, thecompounds of formula I and II are useful to treat cognition disorders incombination with a wide variety of therapeutic agents, in particular, incombination with AMPA potentiators; with typical and atypicalantipsychotics, including olanzapine; with a variety of agents such asmGluR agonists, with NMDA antagonists, with IL 1-6 inhibitors, and thelike; with cholinergics, including cholinesterase inhibitors, such astacrine and donepezil, and compounds that inhibit amyloid proteinprocessing, including inhibitors of amyloid precursor protein processingand antibodies directed against amyloid proteins; with antidepressants,including SSRIs; and with anxiolytic agents; etc. It is believed thatthe combinations above are synergistically beneficial providing efficacyat doses that are a small fraction of those required to produce the sameeffect with the individual components.

As used herein, the term “patient” refers to a warm blooded animal suchas a mammal which is afflicted with one or more disorders associatedwith the 5-HT₆ receptor. It is understood that guinea pigs, dogs, cats,rats, mice, horses, cattle, sheep, pigs, and humans are examples ofanimals within the scope of the meaning of the term.

As used herein, the term “effective amount” of a compound of formula Ior II refers to an amount, that is, the dosage which is effective intreating the disorders described herein.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining an effective amount, the dose of acompound of formula I, a number of factors are considered by theattending diagnostician, including, but not limited to: the compound offormula I or II to be administered; the co-administration of othertherapies, if used; the species of mammal; its size, age, and generalhealth; the specific disorder involved; the degree of involvement or theseverity of the disorder; the response of the individual patient; themode of administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; the use of otherconcomitant medication; and other relevant circumstances.

An effective amount of a compound of formula I and II is expected tovary from about 0.1 milligram per kilogram of body weight per day(mg/kg/day) to about 100 mg/kg/day. Preferred amounts are able to bedetermined by one skilled in the art.

Of the disorders to be treated according to the present invention anumber are particularly preferred.

In a preferred embodiment the present invention provides a method oftreating cognitive disorders, comprising: administering to a patient inneed thereof an effective amount of a compound of claim 1.

In another preferred embodiment the present invention provides a methodfor treating Alzheimer's disease, comprising: administering to a patientin need thereof an effective amount of a compound of formula I.

In a preferred embodiment the present invention provides a method fortreating schizophrenia, comprising: administering to a patient in needthereof an effective amount of a compound of formula I.

The fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV™) (1994, American Psychiatric Association, Washington,D.C.), provides a diagnostic tool including schizophrenia and relateddisorders, all of which are understood to be specifically included inthe scope of this invention.

In a preferred embodiment the present invention provides a method fortreating migraine, comprising: administering to a patient in needthereof an effective amount of a compound of formula I or II or apharmaceutical composition thereof.

In one of the available sources of diagnostic tools, Dorland's MedicalDictionary (23^(rd) Ed., 1982, W. B. Saunders Company, Philadelphia,Pa.), migraine is defined as a symptom complex of periodic headaches,usually temporal and unilateral, often with irritability, nausea,vomiting, constipation or diarrhea, and photophobia. As used herein theterm “migraine” includes to these periodic headaches, both temporal andunilateral, the associated irritability, nausea, vomiting, constipationor diarrhea, photophobia, and other associated symptoms. The skilledartisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, including migraine, and that these systems evolve withmedical scientific progress.

In a preferred embodiment the present invention provides a method fortreating anxiety disorders, including generalized anxiety disorder,panic disorder, and obsessive compulsive disorder, comprising:administering to a patient in need thereof an effective amount of acompound of formula I.

At present, the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool including anxiety andrelated disorders. These include: panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder, generalized anxiety disorder,anxiety disorder due to a general medical condition, substance-inducedanxiety disorder and anxiety disorder not otherwise specified. As usedherein the term “anxiety” includes treatment of those anxiety disordersand related disorders as specifically described in the DSM-IV and theterm “anxiety” is intended to include like disorders that are describedin other diagnostic sources.

A number of preclinical laboratory animal models have been described forthe disorders described herein.

EXAMPLE B

Fear Potentiated Startle Paradigm

Male Sprague-Dawley rats weighing 325-400 g were purchased from HarlanSprague-Dawley, Inc. (Cumberland, Ind.) and given a one week acclimationperiod before testing. Rats were individually housed with food and waterad libitum in an animal room on a 12-hour light/dark cycle with lightson between 6:00 A.M. and 6:00 P.M. The compound of Example 16 wasprepared in a suspension of 5% ethanol, 0.5% CMC, 0.5% Tween 80 and 99%water.2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionicacid was prepared in sterile water. Control rats were given therespective vehicle.

The fear potentiated startle paradigm is conducted over threeconsecutive days. All three days begin with a 5-minute adaptation periodbefore the trial starts. On day one (baseline startle) after theadaptation period, the animal receives 30 trials of 120 dB auditorynoise. The mean startle amplitude (V_(max)) is used to assign animals togroups with similar means before conditioning begins. Day two consistsof conditioning the animals. Each animal receives 0.5 mA of shock for500 msec preceded by a 5 second presentation of light which remains onfor the duration of the shock. Ten presentations of the light and shockare administered. Day three is the testing trial where drugadministration occurs prior to testing. Twenty-four hours afterconditioning, startle testing sessions are conducted. Ten trials ofacoustic startle (120 dB), non-light paired, are presented at thebeginning of the session. This is followed by 20 random trials of thenoise alone and 20 random trials of noise preceded by light. Excludingthe first 10 trials, the startle response amplitudes for each trial typeare averaged for each animal. Data is presented as the differencebetween light+noise and noise-alone. Differences in startle responseamplitudes were analyzed by Jmp statistical software using a One-wayAnova (analysis of variance, t-test). Group differences were consideredto be significant at p<0.05.

The radial arm maze model can be used as a model of cognition and can beused to evaluate the present compounds.

EXAMPLE C

Radial Arm Maze

The delayed non-match to sample task has been used to study the effectof drugs on memory retention (Pussinen, R. and Sirvio, J. J ofPsychopharm 13: 171-179(1999); Staubli, U., et al. Proc Natl Acad Sci91: 777-781(1994)) in the eight arm radial maze.

Well-trained rats were allowed to retrieve food rewards from fourrandomly selected arms of the maze (sampling phase). Some time later,the rats were exposed to eight open arms and were tested for theirability to remember and avoid the arms they had previously entered toobtain food. Re-entry into an arm that was baited during the samplingsession was counted as a reference error, whereas entry into the samearm more than once during the retention session was counted as workingerror. The total (reference+working number of errors made during theretention test increases with increasing delay periods. For example,young male rats made 0.66 (+0.4) errors at a 1 minute delay, 2 (+0.5)errors at a one hour delay, and 3.95 (+0.2) errors at a seven hour delay(observations of this lab).

Male Sprague-Dawley rats were individually housed and maintained on a 12h light-dark cycle (lights on at 6 am). The rats were given free accessto water and maintained at 85% of their free-feeding weight bysupplemental feedings of Purina Lab Chow.

The rats were initially trained to search for food at the end of each ofthe eight arms. Once the rats had reached the criteria of no more thantwo errors (i.e. entering the same arm more than once during a session)on three consecutive days, a delay of one minute was imposed between thefourth and the fifth arm choices. This training ensured that the ratswere thoroughly familiar with the procedural aspects of the task beforeany drugs were administered. Once stable performance had been obtainedon the delay task (i.e. no more than one error was made on threeconsecutive days), drug and vehicle tests commenced using a seven hourdelay period. A novel set of arms was baited each day for each rat andthe maze was thoroughly cleaned during the delay period.

During the sampling session, each rat was placed on the center platformwith access to all eight arms of the maze blocked. Four of the eightarms were randomly selected and baited with food. The gates of thebaited arms were raised and the rat was allowed five minutes to obtainthe food at the end of each of the four arms. As soon as the rat hadobtained the food, it was removed, administered vehicle or various dosesof compounds, and placed back in its home cage. Seven hours later(retention session), the rat was placed back onto the center platformwith access to all eight arms blocked. The four arms that werepreviously baited during the sampling session, were baited and the gatesto all eight arms were raised. The rat was allowed five minutes toobtain the remaining four pieces of food. An entry into a non-baited armor a re-entry into a previously visited arm was counted as an error.Significance (p<0.05) was determined using a repeated measure ANOVAfollowed by a Dunnett's test for comparison with control.

In order to compare test compounds with standards, scopolamine andtacrine were administered s.c. immediately after the sampling phase. Theeffects of scopolamine, a known amnesic, were tested after a three-hourdelay, whereas the effect of tacrine, a cholinesterase inhibitor used inthe treatment of Alzheimer's disease was tested after a six-hour delay.Scopolamine disrupted retention after a three-hour delay in adose-related fashion. Tacrine significantly improved retention after asix-hour delay at 10, but not at 3 mg/kg.

EXAMPLE D

Acquisition in the Radial Maze 8-Arm Radial Maze Acquisition

A prominent early feature of Alzheimer's disease (AD) symptomology is apronounced deficit in declarative memory (R. W. Parks, R. F. Zec & R. S.Wilson (Eds.), Neuropsychology of Alzheimer's disease and otherdementias. NY: Oxford University Press pp. 3-80 (1993).

As the disease progresses, other domains of cognition become severelyaffected as well. Among the brain regions affected early in theprogression of AD is the hippocampus, which is a critical neuralsubstrate for declarative memory (West M. J., Coleman P. D., Flood D. G.& Troncoso J. C. Differences in the pattern of hippocampal neuronal lossin normal aging and Alzheimer's disease. Lancet, 344: 769-772(1994). Onebehavioral test that is often used to assess hippocampal function inanimal models is the 8-arm radial maze (Olton D. S. The radial arm mazeas a tool in behavioral pharmacology. Physiology & Behavior, 40: 793-797(1986)).

Lesions or pharmacological blockade of the hippocampus disruptperformance of this task. Moreover, aged animals generally show deficitsin this task (Porsolt R. D., Roux S. & Wettstein J. G. Animal models ofdementia. Drug Development Research, 35: 214-229(1995)).

In this test of spatial learning and memory, a hungry rat is placed inthe center of the maze and allowed to traverse the maze in search offood located at the end of each runway arm. In this version of the maze,the rat learns a win-shift strategy in which a visited arm is notreplaced. Therefore, the most efficient foraging strategy is to visiteach arm once. The version of the maze also taps into general learningprocesses as the rat is naïve to the maze on day one of the four dayexperiment.

Upon arrival, male Sprague Dawley®, rats were individually housed in aregular light-cycle colony room and allowed to acclimate for at least 4days prior to testing. Each rat was reduced to and maintained at 85% oftheir target body weight throughout the experiment. Proper body weightwas maintained by adjusting the allotment of lab chow based on acombination of age and the rat's daily bodyweight reading.

A session began with an individual rat being placed into the hub of themaze and then all guillotine doors were raised, allowing free access toall areas of the maze. A food hopper was located at the end of each ofthe 8 runway arms and a single food pellet was placed in each foodhopper. Each daily session terminated when either all 8 food-hoppers hadbeen visited or when the rat timed out (15 min on Day 1: 5 min on Days2-4). The number of arm entries was recorded. Errors were counted asrepeat arm entries or failures to visit an arm in the session period. Ananimal was excluded from the study if it failed to visit at least onearm on Day 1, 2 arms on Day 2, and at least 4 arms on Days 3 & 4.

Each rat was pseudo-randomly assigned to either a vehicle or drug groupand received the same treatment throughout the experimental period.Vehicle consisted of 5% acacia within sterile water. Injections wereadministered subcutaneously 20-30 minutes prior to each daily session.

In this acquisition task, vehicle-treated animals do not consistentlyshow significant acquisition of maze learning as compared to the numberof errors committed on Day 1. We have found that in compounds thatfacilitate acquisition of maze learning, the effects are often notobserved until the fourth day of training. Therefore, results consistedof total Day 4 errors across treatment groups.

1. A compound of the formula formula I

wherein X is selected from the group consisting of —O—, —NH—, —S—,—SO2—, —CH2—, —CH(F)—, —CH(OH)—, and —C(O)—; R1 is selected from thegroup consisting of optionally substituted phenyl, optionallysubstituted naphthyl, optionally substituted 5 to 6 membered monocyclicaromatic heterocycle having one heteroatom selected from the groupconsisting of nitrogen, oxygen, and sulfur and which 5 to 6 memberedmonocyclic aromatic heterocycle is optionally benzofused; R2 is selectedfrom the group consisting of hydrogen and C₁-C₃ alkyl; R3 is selectedfrom the group consisting of hydrogen, fluoro, and methyl; R4 isselected from the group consisting of hydrogen, allyl, C2-C4 alkyl,fluorinated C2-C4 alkyl, optionally substituted phenyl, optionallysubstituted phenylsulfonyl, optionally substituted benzyl, andoptionally substituted 5 to 6 membered monocyclic aromatic heterocyclehaving one or two heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, provided that R₄ is not optionallysubstituted phenylsulfonyl when X is —SO2—, —CH2—, CH(F)—, —CH(OH)—, or—C(O)—; and pharmaceutically acceptable salts thereof. 2-56. (canceled)57. A method of treating disorders associated with the 5-HT6 receptor,comprising administering to a patient in need thereof an effectiveamount ofN-(2-(6-Fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.